U.S. patent number RE46,792 [Application Number 15/623,249] was granted by the patent office on 2018-04-17 for oxazole compound and pharmaceutical composition.
This patent grant is currently assigned to Otsuka Pharmaceutical Co., Ltd.. The grantee listed for this patent is Otsuka Pharmaceutical Co., Ltd.. Invention is credited to Junpei Haruta, Hidetaka Hiyama, Masaya Kato, Hideki Kitagaki, Minoru Okada, Norifumi Sato, Tomonori Shibata, Tetsuyuki Uno.
United States Patent |
RE46,792 |
Okada , et al. |
April 17, 2018 |
Oxazole compound and pharmaceutical composition
Abstract
The present invention provides a oxazole compound represented by
Formula (1), or a salt thereof: ##STR00001## wherein R.sup.1 is an
aryl group which may have one or more substituents; R.sup.2 is an
aryl group or a nitrogen atom-containing heterocyclic group each of
which may have one or more substituents; and W is a divalent group
represented by --Y.sup.1-A.sup.1- or or --Y.sup.2--C(.dbd.O)--
wherein Y.sup.1 is a group such as --C(.dbd.O)--, A.sup.1 is a
group such as a lower alkylene group, and Y.sup.2 is a group such
as a piperazinediyl group. The oxazole compound has a specific
inhibitory action against phosphodiesterase 4.
Inventors: |
Okada; Minoru (Ako,
JP), Kato; Masaya (Ako, JP), Sato;
Norifumi (Ako, JP), Uno; Tetsuyuki (Ako,
JP), Kitagaki; Hideki (Ako, JP), Haruta;
Junpei (Ako, JP), Hiyama; Hidetaka (Ako,
JP), Shibata; Tomonori (Ako, JP) |
Applicant: |
Name |
City |
State |
Country |
Type |
Otsuka Pharmaceutical Co., Ltd. |
Tokyo |
N/A |
JP |
|
|
Assignee: |
Otsuka Pharmaceutical Co., Ltd.
(Tokyo, JP)
|
Family
ID: |
37879936 |
Appl.
No.: |
15/623,249 |
Filed: |
June 14, 2017 |
PCT
Filed: |
November 14, 2006 |
PCT No.: |
PCT/JP2006/323066 |
371(c)(1),(2),(4) Date: |
March 26, 2009 |
PCT
Pub. No.: |
WO2007/058338 |
PCT
Pub. Date: |
May 24, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
Reissue of: |
12090951 |
Nov 14, 2006 |
8637559 |
Jan 28, 2014 |
|
|
Foreign Application Priority Data
|
|
|
|
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Nov 15, 2005 [JP] |
|
|
2005-330590 |
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K
31/4709 (20130101); C07D 413/06 (20130101); A61P
19/02 (20180101); C07D 263/34 (20130101); A61P
1/04 (20180101); A61P 11/06 (20180101); C12N
9/16 (20130101); A61P 43/00 (20180101); A61P
27/02 (20180101); C07D 413/06 (20130101); A61P
17/06 (20180101); A61P 25/16 (20180101); A61K
31/496 (20130101); A61P 37/08 (20180101); C07D
263/32 (20130101); C12Y 301/04012 (20130101); C07D
413/12 (20130101); C07D 263/34 (20130101); A61P
11/00 (20180101); A61K 31/4439 (20130101); A61P
17/00 (20180101); A61P 25/18 (20180101); A61P
29/00 (20180101); A61K 31/421 (20130101); C07D
413/12 (20130101); A61P 25/24 (20180101); A61P
25/28 (20180101); A61K 31/497 (20130101); A61P
27/16 (20180101); A61P 37/00 (20180101); A61P
17/14 (20180101); A61P 25/22 (20180101); C07D
263/32 (20130101); A61K 31/5377 (20130101) |
Current International
Class: |
A61K
31/5377 (20060101); C07D 263/34 (20060101); C07D
413/12 (20060101); A61K 31/496 (20060101); A61K
31/4709 (20060101); A61K 31/4439 (20060101); A61K
31/422 (20060101); A61K 31/421 (20060101); C07D
263/32 (20060101); C07D 413/06 (20060101); A61K
31/497 (20060101) |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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10 2004 051277 |
|
Apr 2006 |
|
DE |
|
332332 |
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Sep 1989 |
|
EP |
|
99/KOLNP/2007 |
|
Jun 2007 |
|
IN |
|
11-322730 |
|
Nov 1999 |
|
JP |
|
2001-503022 |
|
Mar 2001 |
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JP |
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2001-519344 |
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Oct 2001 |
|
JP |
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2004-203871 |
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Jul 2004 |
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JP |
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2005-508961 |
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Apr 2005 |
|
JP |
|
WO 96/00218 |
|
Jan 1996 |
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WO |
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WO 98/06830 |
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Mar 1998 |
|
WO |
|
WO 98/08830 |
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Mar 1998 |
|
WO |
|
WO 98/15274 |
|
Apr 1998 |
|
WO |
|
WO 03/072102 |
|
Sep 2003 |
|
WO |
|
WO 2006/019833 |
|
Feb 2006 |
|
WO |
|
WO 2006/045350 |
|
May 2006 |
|
WO |
|
WO 2006103045 |
|
Oct 2006 |
|
WO |
|
Other References
Baumer et al., "Effects of the Phosphodiesterase 4 Inhibitors SB
207499 and and AWD 12-281 on the Inflammatory Reaction in a Model
of Allergic Dermatitis," European Journal of Pharmacology 2002,
446, 195-200. cited by applicant .
Bielekova et al., J. Immunol. 2000. 164, 1117-1124. cited by
applicant .
Blednov et al., Frontiers in Neuroscience 2014, 8, Articie 129,
1-11. cited by applicant .
First Examination Report for corresponding IN Application No.
4398/DELNP/2008 dated Nov. 20, 2013. cited by applicant .
Golub et al., "Molecular Classification of Cancer: Class Discovery
and Class Prediction by Gene Expression Monitoring," Science, vol.
286, Oct. 15, 1999, pp. 531-537. cited by applicant .
Houslay et al., "Phosphodiesterase-4 as a Therapeutic Target," Drug
Discovery Today 2005, 10, 1503-1519. cited by applicant .
International Search Report for PCT/JP2006/323066 dated Apr. 24,
2007. cited by applicant .
Kanes et al., "Rolipram: A Specific Phosphodiesterase 4-Inhibitor
With Potential Antipsychotic Activity," Neuroscience 2007, 144,
239-246. cited by applicant .
Luo et al., "Principles of Cancer Therapy: Oncogene and
Non-oncogene Addiction," Cell 2009, 136, 823-837. cited by
applicant .
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http://www.nhibi.nih.gov/health/health-topics/topics/asthama/prevention
on Jul. 26, 2015. cited by applicant .
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http://www.nhibi.nih.gov/health/health-topics/topics/copd/prevention
on Jul. 26, 2015. cited by applicant .
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applicant .
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337-344. cited by applicant .
Tabei et al., "Ring-transformation of 1,2,4-Oxadiazines. Raney
Nickel Hydrogenation of
Z-3-Aryl-5,6-dihydro-5-(substituted)methylene-4H-1,2,4-oxadiazine
Derivatives [8]," J. Heterocyclic Chem. 1985, 22, 569-574. cited by
applicant .
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cross-coupling for the synthesis of 2,4-disubstituted oxazoles,"
Tetrahedron Letters 2004, 45, 3797-3801. cited by applicant .
Malamas et al. J. Med. Chem. 1996, 39, 237-245. cited by examiner
.
MedlinePlus Medical Dictionary entry for dermatosis, last accessed
Mar. 23, 2010. cited by examiner .
Michael S. Malamas et al., "Azole Phenoxy Hydroxyureas as Selective
and Orally Active Inhibitors of 5-Lipoxygenase," Journal of
Medicinal Chemistry, American Chemical Society, Washington, U.S.
vol. 39, No. 1, 1996, pp. 237-245, XP-002093481. cited by
applicant.
|
Primary Examiner: Johnson; Jerry D
Attorney, Agent or Firm: Finnegan, Henderson, Farabow,
Garrett & Dunner, LLP
Claims
The invention claimed is:
1. An oxazole compound represented by Formula (1) ##STR00296##
wherein R.sup.1 is an aryl group which may have one or more
substituents selected from the following (1-1) to (1-11): (1-1)
hydroxy groups, (1-2) unsubstituted or halogen-substituted lower
alkoxy groups, (1-3) lower alkenyloxy groups, (1-4) lower
alkynyloxy groups, (1-5) cyclo C.sub.3-8 alkyl lower alkoxy groups,
(1-6) cyclo C.sub.3-8 alkyloxy groups, (1-7) cyclo C.sub.3-8
alkenyloxy groups, (1-8) dihydroindenyloxy groups, (1-9) hydroxy
lower alkoxy groups, (1-10) oxiranyl lower alkoxy groups, and
(1-11) protected hydroxy groups; R.sup.2 is an aryl group or a
nitrogen atom-containing heterocyclic group each of which may have
one or more substituents selected from the following (2-1) to
(2-10): (2-1) hydroxy groups, (2-2) unsubstituted or
halogen-substituted lower alkoxy groups, (2-3) unsubstituted lower
alkyl groups, (2-4) lower alkenyloxy groups, (2-5) halogen atoms,
(2-6) lower alkanoyl groups other than a formyl group, (2-7) lower
alkylthio groups, (2-8) lower alkylsulfonyl groups, (2-9) oxo
groups, and (2-10) lower alkoxy lower alkoxy groups; and the
nitrogen atom-containing heterocyclic group in R.sup.2 is selected
from imidazolidinyl, hexahydropyrimidinyl, piperazinyl,
octahydroisoindolyl, azocanyl, pyrrolyl, dihydropyrrolyl,
imidazolyl, dihydroimidazolyl, triazolyl, dihydrotriazolyl,
pyrazolyl, pyridyl and N-oxides thereof, dihydropyridyl,
pyrimidinyl, dihydropyrimidinyl, pyrazinyl, dihydropyrazinyl,
pyridazinyl, tetrazolyl, indolyl, isoindolyl, indolinyl,
isoindolinyl, hexahydroisoindolinyl, benzoimidazolyl, quinolyl,
isoquinolyl, indazolyl, quinazolinyl, dihydroquinazolinyl,
benzotriazolyl, carbazolyl, oxazolyl, isooxazolyl, oxadiazolyl,
oxazolidinyl, isooxazolidinyl, dihydrobenzoxazolyl, benzoxazinyl,
dihydrobenzoxazinyl, benzoxazolyl, benzooxadiazolyl, thiazolyl,
dihydrothiazolyl, isothiazolyl, thiadiazolyl, dihydrothiazinyl,
thiazolyzinyl, benzothiazolyl, and benzothiadiazolyl; and W is a
divalent group represented by Formula (i) or (ii):
--Y.sup.1-A.sup.1- Formula (i) --Y.sup.2--C(.dbd.O)-- Formula (ii)
wherein A.sup.1 is a lower alkenylene group, or a lower alkylene
group which may have one or more substituents selected from the
group consisting of hydroxy groups and lower alkoxycarbonyl groups,
Y.sup.1 is --C(.dbd.O)--, --C(.dbd.O)--N(R.sup.3)--,
--S(O).sub.m--NH--, or --S(O).sub.n-- wherein R.sup.3 is a hydrogen
atom or a lower alkyl group, and m and n are each independently an
integer from 0 to 2, and Y.sup.2 is a piperazinediyl group, or a
divalent group represented by Formula (iii):
--C(.dbd.O)-A.sup.2-N(R.sup.5)-- Formula (iii) wherein A.sup.2 is a
lower alkylene group, and R.sup.5 is a hydrogen atom or a lower
alkyl group; or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1, wherein R.sup.1 is a phenyl
group which has 1 to 3 substituents selected from the following
(1-2), (1-3), (1-4) and (1-5): (1-2) unsubstituted or
halogen-substituted lower alkoxy groups, (1-3) lower alkenyloxy
groups, (1-4) lower alkynyloxy groups, and (1-5) cyclo C.sub.3-8
alkyl lower alkoxy groups; R.sup.2 is a phenyl group or a pyridyl
group each of which may have 1 to 3 substituents selected from the
group consisting of the following (2-2), (2-3), (2-4) and (2-5):
(2-2) unsubstituted or halogen-substituted lower alkoxy groups,
(2-3) unsubstituted lower alkyl groups, (2-4) lower alkenyloxy
groups, and (2-5) halogen atoms; W is a divalent group represented
by Formula (i): --Y.sup.1-A.sup.1- Formula (i) wherein A.sup.1 is a
lower alkylene group, and Y.sup.1 is --C(.dbd.O)-- or
.Iadd.--C(.dbd.O)--N(R.sup.3)--.Iaddend. wherein R.sup.3 is a
hydrogen atom.
3. The compound according to claim 2, wherein R.sup.1 is a phenyl
group having two substituents selected from the following (1-2),
(1-3), (1-4) and (1-5): (1-2) unsubstituted or halogen-substituted
lower alkoxy groups, (1-3) lower alkenyloxy groups, (1-4) lower
alkynyloxy groups, and (1-5) cyclo C.sub.3-8 alkyl lower alkoxy
groups; R.sup.2 is a phenyl group or a pyridyl group each of which
may have 1 to 2 substituents selected from the following (2-2),
(2-3), (2-4) and (2-5): (2-2) unsubstituted or halogen-substituted
lower alkoxy groups, (2-3) unsubstituted lower alkyl groups, (2-4)
lower alkenyloxy groups, and (2-5) halogen atoms; and W is a
divalent group represented by Formula (i): --Y.sup.1-A.sup.1-
Formula (i) wherein A.sup.1 is a lower alkylene group, and Y.sup.1
is .[.--C(O)--.]. .Iadd.--C(.dbd.O)-- .Iaddend.or
--C(.dbd.O)--N(R.sup.3)-- wherein R.sup.3 is a hydrogen atom.
4. The compound according to claim 3, wherein R.sup.1 is a phenyl
group substituted on the phenyl ring with two lower alkoxy groups,
a phenyl group substituted on the phenyl ring with one lower alkoxy
group and one cyclo .[.C.sub.3-8,.]. .Iadd.C.sub.3-8 .Iaddend.alkyl
lower alkoxy group, a phenyl group substituted on the phenyl ring
with one lower alkoxy group and one halogen-substituted lower
alkoxy group, a phenyl group substituted on the phenyl group with
one lower alkoxy group and one lower alkenyloxy group, a phenyl
group substituted on the phenyl ring with one halogen-substituted
lower alkoxy group and one cyclo C.sub.3-8 alkyl lower alkoxy
group, a phenyl group substituted on the phenyl ring with one
halogen-substituted lower alkoxy group and one lower alkenyloxy
group, or a phenyl group substituted on the phenyl ring with two
halogen-substituted lower alkoxy groups; R.sup.2 is a lower
alkoxyphenyl group, a lower alkenyloxyphenyl group, a
halogen-substituted lower alkoxyphenyl group, a lower alkylpyridyl
group, or a phenyl group substituted on the phenyl ring with one
lower alkoxy group and one halogen atom; and W is a divalent group
represented by Formula (i): --Y.sup.1-A.sup.1- Formula (i) wherein
A.sup.1 is a C.sub.1-4 alkylene group, and Y.sup.1 is --C(.dbd.O)--
or --C(.dbd.O)--N(R.sup.3)-- wherein R.sup.3 is a hydrogen
atom.
5. The compound according to claim 4, wherein R.sup.1 is a phenyl
group substituted on the phenyl ring with two lower alkoxy groups,
a phenyl group substituted on the phenyl ring with one lower alkoxy
group and one cyclo C.sub.3-8 alkyl lower alkoxy group, a phenyl
group substituted on the phenyl ring with one lower alkoxy group
and one halogen-substituted lower alkoxy group, a phenyl group
substituted on the phenyl group with one lower alkoxy group and one
lower alkenyloxy group, a phenyl group substituted on the phenyl
ring with one halogen-substituted lower alkoxy group and one cyclo
C.sub.3-8 alkyl lower alkoxy group, a phenyl group substituted on
the phenyl ring with one halogen-substituted lower alkoxy group and
one lower alkenyloxy group, or a phenyl group substituted on the
phenyl ring with two halogen-substituted lower alkoxy groups;
R.sup.2 is a lower alkoxyphenyl group, a lower alkenyloxy phenyl
group, a halogen-substituted lower alkoxyphenyl group, a lower
alkylpyridyl group, or a phenyl group substituted on the phenyl
ring with one lower alkoxy group and one halogen atom; and W is a
divalent group represented by Formula (i): --Y.sup.1-A.sup.1-
Formula (i) wherein A.sup.1 is a C.sub.1-4 alkylene group, and
Y.sup.1 is --C(.dbd.O)--.
6. The compound according to claim 4, wherein R.sup.1 is a phenyl
group substituted on the phenyl ring with one lower alkoxy group
and one halogen-substituted lower alkoxy group, a phenyl group
substituted on the phenyl ring with one halogen-substituted lower
alkoxy group and one cyclo C.sub.3-8 alkyl lower alkoxy group, or a
phenyl group substituted on the phenyl ring with one
halogen-substituted lower alkoxy group and one lower alkenyloxy
group; R.sup.2 is a lower alkoxyphenyl group or a lower
alkylpyridyl group; and W is a divalent group represented by
Formula (i): --Y.sup.1-A.sup.1- Formula (i) wherein A.sup.1 is a
C.sub.1-4 alkylene group, and Y.sup.1 is --C(.dbd.O)--N(R.sup.3)--
wherein R.sup.3 is a hydrogen atom.
7. A pharmaceutical composition comprising the compound or a
pharmaceutically acceptable salt according to any one of claims 1
to 6 as an active ingredient and a pharmaceutically acceptable
carrier.
8. A method for treating dermatosis, the method comprising
administering the compound or a pharmaceutically acceptable salt
according to any one of claims 1 to 6 to a human or an animal in
need thereof.
9. A process for producing an oxazole compound represented by
Formula (1): ##STR00297## wherein R.sup.1, R.sup.2 and W are the
same as defined in claim 1, or a salt thereof, the process
comprising a reaction of a compound represented by Formula (2):
##STR00298## wherein R.sup.2 and W are the same as defined above,
and X is a halogen atom, or a pharmaceutically acceptable salt
thereof, with a compound represented by Formula (3): ##STR00299##
wherein R.sup.1 is the same as defined above, or a salt
thereof.
10. The compound or a pharmaceutically acceptable salt thereof
according to claim 6, which is selected from the group consisting
of the following compounds:
.[.N-[2-(4-difluoromethoxy-3-isobutoxyphenyl)oxazol-4-yl ethyl
p-methylpicolinamide,.].
.Iadd.N-[2-(4-difluoromethoxy-3-isobutoxyphenyl)oxazol-4-ylmethyl]-3-meth-
ylpicolinamide, .Iaddend.
N-[2-(3-cyclobutylmethoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-3-me-
thylpicolinamide,
N-[2-(4-difluoromethoxy-3-isobutoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenz-
amide,
N-[2-(4-difluoromethoxy-3-ethoxyphenyl)oxazol-4-ylmethyl]-2-ethoxyb-
enzamide,
N-[2-(3-allyloxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-et-
hoxybenzamide,
.[.N-[2-(4-difluoromethoxy-3-isopropoxyphenyl)oxazol-4-ylmethyl]2-ethoxyb-
enzamide, N-[2-(3-cyclopropylmethoxy-4-d
fluoromethoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide, and.].
.Iadd.N-[2-(4-difluoromethoxy-3-isopropoxyphenyl)oxazol-4-ylmethyl]-2-eth-
oxybenzamine,
N-[2-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-e-
thoxybenzamide, and .Iaddend.
N-[2-(3-but-3-enyloxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-ethoxy-
benzamide.
.Iadd.11. A compound which is
N-[2-(4-difluoromethoxy-3-isopropoxyphenyl)oxazol-4-ylmethyl]-2-ethoxyben-
zamide, having the structure: ##STR00300## .Iaddend.
.Iadd.12. A pharmaceutical composition comprising the compound
according to claim 11 as an active ingredient and a
pharmaceutically acceptable carrier. .Iaddend.
.Iadd.13. A method for treating dermatosis, the method comprising
administering the compound according to claim 11 to a human or an
animal in need thereof. .Iaddend.
.Iadd.14. A pharmaceutically acceptable salt of a compound, the
compound being
N-[2-(4-difluoromethoxy-3-isopropoxyphenyl)oxazol-4-ylmethyl]-2-eth-
oxybenzamide and having the structure: ##STR00301## .Iaddend.
.Iadd.15. A pharmaceutical composition comprising the
pharmaceutically acceptable salt according to claim 14 as an active
ingredient and a pharmaceutically acceptable carrier. .Iaddend.
.Iadd.16. A method for treating dermatosis, the method comprising:
administering the pharmaceutically acceptable salt according to
claim 14 to a human or an animal in need thereof. .Iaddend.
Description
.Iadd.This patent application is a reissue application of U.S. Pat.
No. 8,637,559, issued Jan. 28, 2014, on application Ser. No.
12/090,951, .sctn. 371(c) date of Mar. 26, 2009, which is the
National Stage of PCT/JP2006/323066, filed Nov. 14, 2006.
.Iaddend.
TECHNICAL FIELD
The present invention relates to new oxazole compounds and
pharmaceutical compositions.
BACKGROUND ART
Various oxazole compounds have been developed and are disclosed in
documents such as WO 03/072102, WO 98/15274, etc. However, the
oxazole compounds of the present invention are not disclosed in any
literature.
Some compounds having a specific inhibitory action against
phosphodiesterase 4 (PDE4) have been reported. However, known PDE4
inhibitors have problems of side effects such as vomit induction,
nausea, etc. and/or a defect of insufficient PDE4 inhibitory
action. Therefore, known PDE4 inhibitors are not clinically used as
therapeutic agents.
DISCLOSURE OF THE INVENTION
An object of the present invention is to provide a compound that
has a PDE4 inhibitory action and is free from the above-mentioned
problems of the prior art.
The present inventors conducted extensive research to solve the
above problems, and succeeded in synthesizing an oxazole compound
with a novel structure, the compound having high specificity and a
strong PDE4 inhibitory action. Further, the present inventors found
that the oxazole compound is capable of exhibiting preventive
and/or therapeutic effects on PDE-mediated diseases, and in
particular atopic dermatitis, based on its PDE4 inhibitory action.
Furthermore, the inventors found that the compound has low
penetration into blood when administered transdermally, and thus
has low systemic side effects.
The present inventors further found that the oxazole compound is
capable of exhibiting a tumor necrosis factor-.alpha. (TNF-.alpha.)
production inhibitory action.
In chronic inflammatory diseases such as autoimmune diseases and
allergic diseases, cytokines produced by immunocompetent cells are
known to be important inflammatory mediators, and among such
cytokines, TNF-.alpha. is presumed to play a particularly important
role. Therefore, the oxazole compound of the present invention is
extremely effective for the treatment of TNF-.alpha.-mediated
diseases.
The present invention has been accomplished by further research
based on the above findings.
The present invention provides a oxazole compound, a pharmaceutical
composition comprising said compound, a use of said compound, a
method for treating or preventing a disorder, and a process for
producing said compound, as described in Item 1 to 14 below.
Item 1. An oxazole compound represented by Formula (1)
##STR00002## wherein R.sup.1 is an aryl group which may have one or
more substituents selected from the following (1-1) to (1-11):
(1-1) hydroxy groups, (1-2) unsubstituted or halogen-substituted
lower alkoxy groups, (1-3) lower alkenyloxy groups, (1-4) lower
alkynyloxy groups, (1-5) cyclo C.sub.3-8 alkyl lower alkoxy groups,
(1-6) cyclo C.sub.3-8 alkyloxy groups, (1-7) cyclo C.sub.3-8
alkenyloxy groups, (1-8) dihydroindenyloxy groups, (1-9) hydroxy
lower alkoxy groups, (1-10) oxiranyl lower alkoxy groups, and
(1-11) protected hydroxy groups; R.sup.2 is an aryl group or a
nitrogen atom-containing heterocyclic group each of which may have
one or more substituents selected from the following (2-1) to
(2-10): (2-1) hydroxy groups, (2-2) unsubstituted or
halogen-substituted lower alkoxy groups, (2-3) unsubstituted or
halogen-substituted lower alkyl groups, (2-4) lower alkenyloxy
groups, (2-5) halogen atoms, (2-6) lower alkanoyl groups, (2-7)
lower alkylthio groups, (2-8) lower alkylsulfonyl groups, (2-9) oxo
groups, and (2-10) lower alkoxy lower alkoxy groups; and W is a
divalent group represented by Formula (i) or (ii): Formula (i)
--Y.sup.1-A.sup.1- Formula (ii) --Y.sup.2--C(.dbd.O)-- wherein
A.sup.1 is a lower alkenylene group, or a lower alkylene group
which may have one or more substituents selected from the group
consisting of hydroxy groups and lower alkoxycarbonyl groups,
Y.sup.1 is a direct bond, --C(.dbd.O)--, --C(.dbd.O)--N(R.sup.3)--,
--N(R.sup.4)--C(.dbd.O)--, --S(O).sub.m--NH--, or --S(O).sub.n--
wherein R.sup.3 and R.sup.4 are each independently a hydrogen atom
or a lower alkyl group, and m and n are each independently an
integer from 0 to 2, and Y.sup.2 is a piperazinediyl group, or a
divalent group represented by Formula (iii) or (iv): Formula (iii)
--C(.dbd.O)-A.sup.2-N(R.sup.5)-- Formula (iv) -A.sup.3-N(R.sup.6)--
wherein A.sup.2 and A.sup.3 are each independently a lower alkylene
group, and R.sup.5 and R.sup.6 are each independently a hydrogen
atom or a lower alkyl group; or a salt thereof.
Item 2. The compound according to item 1, wherein R.sup.1 is a
phenyl group which has 1 to 3 substituents selected from the
following (1-2), (1-3), (1-4) and (1-5):
(1-2) unsubstituted or halogen-substituted lower alkoxy groups,
(1-3) lower alkenyloxy groups,
(1-4) lower alkynyloxy groups, and
(1-5) cyclo C.sub.3-8 alkyl lower alkoxy groups;
R.sup.2 is a phenyl group or a pyridyl group each of which may have
1 to 3 substituents selected from the group consisting of the
following (2-2), (2-3), (2-4) and (2-5):
(2-2) unsubstituted or halogen-substituted lower alkoxy groups,
(2-3) unsubstituted or halogen-substituted lower alkyl groups,
(2-4) lower alkenyloxy groups, and
(2-5) halogen atoms;
W is a divalent group represented by Formula (i):
--Y.sup.1-A.sup.1- Formula (i) wherein A.sup.1 is a lower alkylene
group, and Y.sup.1 is --C(.dbd.O)-- or --C(.dbd.O)--N(R.sup.3)--
wherein R.sup.3 is a hydrogen atom.
Item 3. The compound according to item 2, wherein R.sup.1 is a
phenyl group having two substituents selected from the following
(1-2), (1-3), (1-4) and (1-5):
(1-2) unsubstituted or halogen-substituted lower alkoxy groups,
(1-3) lower alkenyloxy groups,
(1-4) lower alkynyloxy groups, and
(1-5) cyclo C.sub.3-8 alkyl lower alkoxy groups;
R.sup.2 is a phenyl group or a pyridyl group each of which may have
1 to 2 substituents selected from the following (2-2), (2-3), (2-4)
and (2-5):
(2-2) unsubstituted or halogen-substituted lower alkoxy groups,
(2-3) unsubstituted or halogen-substituted lower alkyl groups,
(2-4) lower alkenyloxy groups, and
(2-5) halogen atoms; and
W is a divalent group represented by Formula (i):
--Y.sup.1-A.sup.1- Formula (i) wherein A.sup.1 is a lower alkylene
group, and Y.sup.1 is --C(.dbd.O)-- or --C(.dbd.O)--N(R.sup.3)--
wherein R.sup.3 is a hydrogen atom.
Item 4. The compound according to item 3, wherein R.sup.1 is a
phenyl group substituted on the phenyl ring with two lower alkoxy
groups, a phenyl group substituted on the phenyl ring with one
lower alkoxy group and one Cyclo C.sub.3-8 alkyl lower alkoxy
group, a phenyl group substituted on the phenyl ring with one lower
alkoxy group and one halogen-substituted lower alkoxy group, a
phenyl group substituted on the phenyl group with one lower alkoxy
group and one lower alkenyloxy group, a phenyl group substituted on
the phenyl ring with one halogen-substituted lower alkoxy group and
one cyclo C.sub.3-8 alkyl lower alkoxy group, a phenyl group
substituted on the phenyl ring with one halogen-substituted lower
alkoxy group and one lower alkenyloxy group, or a phenyl group
substituted on the phenyl ring with two halogen-substituted lower
alkoxy groups;
R.sup.2 is a lower alkoxyphenyl group, a lower alkenyloxyphenyl
group, a halogen-substituted lower alkoxyphenyl group, a lower
alkylpyridyl group, or a phenyl group substituted on the phenyl
ring with one lower alkoxy group and one halogen atom; and
W is a divalent group represented by Formula (i):
--Y.sup.1-A.sup.1- Formula (i) wherein A.sup.1 is a C.sub.1-4
alkylene group, and Y.sup.1 is --C(.dbd.O)-- or
--C(.dbd.O)--N(R.sup.3)-- wherein R.sup.3 is a hydrogen atom.
Item 5. The compound according to item 4, wherein R.sup.1 is a
phenyl group substituted on the phenyl ring with two lower alkoxy
groups, a phenyl group substituted on the phenyl ring with one
lower alkoxy group and one cyclo C.sub.3-8 alkyl lower alkoxy
group, a phenyl group substituted on the phenyl ring with one lower
alkoxy group and one halogen-substituted lower alkoxy group, a
phenyl group substituted on the phenyl group with one lower alkoxy
group and one lower alkenyloxy group, a phenyl group substituted on
the phenyl ring with one halogen-substituted lower alkoxy group and
one cyclo C.sub.3-8 alkyl lower alkoxy group, a phenyl group
substituted on the phenyl ring with one halogen-substituted lower
alkoxy group and one lower alkenyloxy group, or a phenyl group
substituted on the phenyl ring with two halogen-substituted lower
alkoxy groups;
R.sup.2 is a lower alkoxyphenyl group, a lower alkenyloxy phenyl
group, a halogen-substituted lower alkoxyphenyl group, a lower
alkylpyridyl group, or a phenyl group substituted on the phenyl
ring with one lower alkoxy group and one halogen atom; and
W is a divalent group represented by Formula (i) --Y.sup.1-A.sup.1-
Formula (i) wherein A.sup.1 is a C.sub.1-4 alkylene group, and
Y.sup.1 is --C(.dbd.O)--.
Item 6. The compound according to item 4, wherein R.sup.1 is a
phenyl group substituted on the phenyl ring with one lower alkoxy
group and one halogen-substituted lower alkoxy group, a phenyl
group substituted on the phenyl ring with one halogen-substituted
lower alkoxy group and one cyclo C.sub.3-8 alkyl lower alkoxy
group, or a phenyl group substituted on the phenyl ring with one
halogen-substituted lower alkoxy group and one lower alkenyloxy
group;
R.sup.2 is a lower alkoxyphenyl group or a lower alkylpyridyl
group; and
W is a divalent group represented by Formula (i):
--Y.sup.1-A.sup.1- Formula (i) wherein A.sup.1 is a C.sub.1-4
alkylene group, and Y.sup.1 is --C(.dbd.O)--N(R.sup.3)-- wherein
R.sup.3 is a hydrogen atom.
Item 7. A pharmaceutical composition comprising the compound or
salt according to any one of items 1 to 6 as an active ingredient
and a pharmaceutically acceptable carrier.
Item 8. A pharmaceutical composition for treating or preventing
phosphodiesterase 4-mediated and/or tumor necrosis
factor-.alpha.-mediated diseases, the composition comprising the
compound or salt according to any one of items 1 to 6.
Item 9. A pharmaceutical composition for treating or preventing
atopic dermatitis, the composition comprising the compound or salt
according to any one of items 1 to 6.
Item 10. A process for producing a pharmaceutical composition, the
process comprising mixing the compound or salt according to any one
of items 1 to 6 with a pharmaceutically acceptable carrier.
Item 11. Use of the compound or salt according to any one of items
1 to 6 as a drug.
Item 12. Use of the compound or salt according to any one of items
1 to 6 as a phosphodiesterase 4 inhibitor and/or tumor necrosis
factor-.alpha. production inhibitor.
Item 13. A method for treating or preventing phosphodiesterase
4-mediated and/or tumor necrosis factor-.alpha.-mediated diseases,
the method comprising administering the compound or salt according
to any one of items 1 to 6 to human or animal.
Item 14. A process for producing an oxazole compound represented by
Formula (1):
##STR00003## wherein R.sup.1, R.sup.2 and W are the same as defined
in item 1, or a salt thereof, the process comprising a reaction of
a compound represented by Formula (2):
##STR00004## wherein R.sup.2 and W are the same as defined above,
and X is a halogen atom, or a salt thereof, with a compound
represented by Formula (3):
##STR00005## wherein R.sup.1 is the same as defined above, or a
salt thereof.
In Formula (1), R.sup.1 is preferably a phenyl group. The phenyl
group represented by R.sup.1 preferably has 1 to 3, and more
preferably 2, substituents selected from the group consisting of
(1-2) unsubstituted or halogen-substituted lower alkoxy groups,
(1-3) lower alkenyloxy groups, (1-4) lower alkynyloxy groups, and
(1-5) cyclo C.sub.3-8 alkyl lower alkoxy groups.
In Formula (1), R.sup.2 is preferably a phenyl group or a pyridyl
group. The phenyl group or pyridyl group represented by R.sup.2
preferably has 1 to 3, and more preferably 1, substituents selected
from the group consisting of (2-2) unsubstituted or
halogen-substituted lower alkoxy groups, (2-3) unsubstituted or
halogen-substituted lower alkyl groups, (2-4) lower alkenyloxy
groups, and (2-5) halogen atoms.
In Formula (1), W is preferably a divalent group represented by
Formula (i) --Y.sup.1-A.sup.1-. A is preferably a lower alkylene
group; Y.sup.1 is preferably --C(.dbd.O)-- or
--C(.dbd.O)--N(R.sup.3)--; and R.sup.3 is preferably a hydrogen
atom.
Among the oxazole compounds of the present invention, those
represented by Formula (1A) and salts thereof are preferable, and
those represented by Formula (1B) and salts thereof are more
preferable.
Formula (1A):
##STR00006## wherein R.sup.1 is a phenyl group having two
substituents selected from the following (1-2), (1-3), (1-4) and
(1-5): (1-2) unsubstituted or halogen-substituted lower alkoxy
groups, (1-3) lower alkenyloxy groups, (1-4) lower alkynyloxy
groups, and (1-5) cyclo C.sub.3-8 alkyl lower alkoxy groups;
R.sup.2 is a phenyl group or a pyridyl group each of which may have
one or more substituents selected from the following (2-2), (2-3),
(2-4) and (2-5): (2-2) unsubstituted or halogen-substituted lower
alkoxy groups, (2-3) unsubstituted or halogen-substituted lower
alkyl groups, (2-4) lower alkenyloxy groups, and (2-5) halogen
atoms; and W is a divalent group represented by Formula (i):
--Y.sup.1-A.sup.1- Formula (i) wherein A.sup.1 is a lower alkylene
group, and Y.sup.1 is --C(.dbd.O)-- or --C(.dbd.O)--N(R.sup.3)--
wherein R.sup.3 is a hydrogen atom.
Formula (1B):
##STR00007## wherein R.sup.1 is a phenyl group substituted on the
phenyl ring with two lower alkoxy groups, a phenyl group
substituted on the phenyl ring with one lower alkoxy group and one
cyclo C.sub.3-8 alkyl lower alkoxy group, a phenyl group
substituted on the phenyl ring with one lower alkoxy group and one
halogen-substituted lower alkoxy group, a phenyl group substituted
on the phenyl group with one lower alkoxy group and one lower
alkenyloxy group, a phenyl group substituted on the phenyl ring
with one halogen-substituted lower alkoxy group and one cyclo
C.sub.3-8 alkyl lower alkoxy group, a phenyl group substituted on
the phenyl ring with one halogen-substituted lower alkoxy group and
one lower alkenyloxy group, or a phenyl group substituted on the
phenyl ring with two halogen-substituted lower alkoxy groups;
R.sup.2 is a lower alkoxyphenyl group, a lower alkenyloxyphenyl
group, a halogen-substituted lower alkoxyphenyl group, a lower
alkylpyridyl group, or a phenyl group substituted on the phenyl
ring with one lower alkoxy group and one halogen atom; and W is a
divalent group represented by Formula (i): --Y.sup.1-A.sup.1-
Formula (i) wherein A.sup.1 is a C.sub.1-4 alkylene group, and
Y.sup.1 is --C(.dbd.O)-- or --C(.dbd.O)--N(R.sup.3)-- wherein
R.sup.3 is a hydrogen atom.
The present invention is described below in further detail.
Compound Represented by Formula (1)
In Formula (1), R.sup.1 is an aryl group. The aryl group may have 1
to 3, and preferably 2, substituents selected from the group
consisting of (1-1) hydroxy groups, (1-2) unsubstituted or
halogen-substituted lower alkoxy groups, (1-3) lower alkenyloxy
groups, (1-4) lower alkynyloxy groups, (1-5) cyclo C.sub.3-8 alkyl
lower alkoxy groups, (1-6) cyclo C.sub.3-8 alkyloxy groups, (1-7)
cyclo C.sub.3-8 alkenyloxy groups, (1-8) dihydroindenyloxy groups,
(1-9) hydroxy lower alkoxy groups, (1-10) oxiranyl lower alkoxy
groups, and (1-11) protected hydroxy groups.
In Formula (1), R.sup.2 is an aryl group or a nitrogen
atom-containing heterocyclic group. The aryl group and heterocyclic
group may have 1 to 3, and preferably 1, substituent selected from
the group consisting of (2-1) hydroxy groups, (2-2) unsubstituted
or halogen-substituted lower alkoxy groups, (2-3) unsubstituted or
halogen-substituted lower alkyl groups, (2-4) lower alkenyloxy
groups, (2-5) halogen atoms, (2-6) lower alkanoyl groups, (2-7)
lower alkylthio groups, (2-8) lower alkylsulfonyl groups, (2-9) oxo
groups, and (2-10) lower alkoxy lower alkoxy groups.
In Formula (1), W is a divalent group represented by Formula (i) or
(ii): --Y.sup.1-A.sup.1- Formula (i) --Y.sup.2--C(.dbd.O)-- Formula
(ii) wherein A.sup.1 is a lower alkenylene group, or a lower
alkylene group which may have 1 to 3, and preferably 1, substituent
selected from the group consisting of hydroxy groups and lower
alkoxycarbonyl groups; Y.sup.1 is a direct bond, --C(.dbd.O)--,
--C(.dbd.O)--N(R.sup.3)--, --N(R.sup.4)--C(.dbd.O)--,
--S(O).sub.m--NH--, or --S(O).sub.n-- wherein R.sup.3 and R.sup.4
are each independently a hydrogen atom or a lower alkyl group, and
m and n are each independently an integer from 0 to 2; and Y.sup.2
is a piperazinediyl group, or a divalent group represented by
Formula (iii) or (iv): --C(.dbd.O)-A.sup.2-N(R.sup.5)-- Formula
(iii) -A.sup.3-N(R.sup.6)-- Formula (iv) wherein A.sup.2 and
A.sup.3 are each independently a lower alkylene group, and R.sup.5
and R.sup.6 are each independently a hydrogen atom or a lower alkyl
group.
Examples of aryl groups include phenyl, naphthyl, etc.
Examples of halogen atoms include fluorine, chlorine, bromine,
iodine, etc.
Lower alkyl groups are straight- or branched-chain alkyl groups
having 1 to 6 carbon atoms, and examples thereof include methyl,
ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl,
sec-butyl, 1-ethylpropyl, n-pentyl, neopentyl, n-hexyl, isohexyl,
3-methylpentyl, etc.
Unsubstituted or halogen-substituted lower alkyl groups are
straight- or branched-chain alkyl groups having 1 to 6 carbon atoms
as defined above, or such alkyl groups substituted with 1 to 7
halogen atoms. Examples thereof include methyl, ethyl, n-propyl,
isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, 1-ethylpropyl,
n-pentyl, neopentyl, n-hexyl, isohexyl, 3-methyl pentyl,
fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,
dichloromethyl, trichloromethyl, bromomethyl, dibromomethyl,
dichlorofluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl,
2,2,2-trifluoroethyl, pentafluoroethyl, 2-chloroethyl,
3,3,3-trifluoropropyl, heptafluoropropyl, heptafluoroisopropyl,
3-chloropropyl, 2-chloropropyl, 3-bromopropyl,
4,4,4-trifluorobutyl, 4,4,4,3,3-pentafluorobutyl, 4-chlorobutyl,
4-bromobutyl, 2-chlorobutyl, 5,5,5-trifluoropentyl, 5-chloropentyl,
6,6,6-trifluorohexyl, 6-chlorohexyl, etc.
Lower alkenyloxy groups are groups composed of an oxygen atom and a
C.sub.2-6 straight- or branched-chain alkenyl group having 1 to 3
double bonds. Lower alkenyloxy groups have cis and trans forms.
More specific examples thereof include vinyloxy, 1-propenyloxy,
2-propenyloxy, 1-methyl-1-propenyloxy, 2-methyl-1-propenyloxy,
2-methyl-2-propenyloxy, 2-propenyloxy, 2-butenyloxy, 1-butenyloxy,
3-butenyloxy, 2-pentenyloxy, 1-pentenyloxy, 3-pentenyloxy,
4-pentenyloxy, 1,3-butadienyloxy, 1,3-pentadienyloxy,
2-penten-4-yloxy, 3-methyl-2-butenyloxy, 2-hexenyloxy,
1-hexenyloxy, 5-hexenyloxy, 3-hexenyloxy, 4-hexenyloxy,
3,3-dimethyl-1-propenyloxy, 2-ethyl-1-propenyloxy,
1,3,5-hexatrienyloxy, 1,3-hexadienyloxy, 1,4-hexadienyloxy,
etc.
Examples of lower alkynyloxy groups include groups composed of an
oxygen atom and a C.sub.2-6 straight- or branched-chain alkynyl
group having 1 to 3 triple bonds. More specific examples thereof
include ethynyloxy, 2-propynyloxy, 2-butynyloxy, 3-butynyloxy,
1-methyl-2-propynyloxy, 2-pentynyloxy, 2-hexynyloxy, etc.
Examples of cyclo C.sub.3-8 alkyl groups include cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,
etc.
Preferable examples of lower alkoxy groups include C.sub.1-6
straight- or branched-chain alkoxy groups. Specifically, such
groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,
isobutoxy, tert-butoxy, sec-butoxy, 1-ethylpropoxy, n-pentoxy,
neopentoxy, n-hexyloxy, isohexyloxy, 3-methylpentoxy, etc.
Examples of cyclo C.sub.3-8 alkyl lower alkoxy groups include the
above-mentioned lower alkoxy groups which have 1 to 3, and
preferably 1, cyclo C.sub.3-8 alkyl group as listed above. More
specific examples thereof include cyclopropylmethoxy,
cyclobutylmethoxy, cyclohexylmethoxy, 2-cyclopropylethoxy,
1-cyclobutylethoxy, cyclopentylmethoxy, 3-cyclopentylpropoxy,
4-cyclohexylbutoxy, 5-cycloheptylpentoxy, 6-cyclooctylhexyloxy,
1,1-dimethyl-2-cyclohexylethoxy, 2-methyl-3-cyclopropylpropoxy,
etc.
Examples of cyclo C.sub.3-8 alkyloxy groups include cyclopropyloxy,
cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy,
cyclooctyloxy, etc.
Examples of cyclo C.sub.3-8 alkenyloxy groups include
cyclopropenyloxy, cyclobutenyloxy, cyclopentenyloxy,
cyclohexenyloxy, cycloheptenyloxy, cyclooctenyloxy, etc.
Examples of dihydroindenyloxy groups include
2,3-dihydroinden-1-yloxy, 2,3-dihydroinden-2-yloxy, etc.
Examples of hydroxy lower alkoxy groups include lower alkoxy groups
(preferably C.sub.1-6 straight- or branched-chain alkoxy groups)
having 1 to 5, and preferably 1 to 3, hydroxy groups. More specific
examples thereof include hydroxymethyloxy, 2-hydroxyethyloxy,
1-hydroxyethyloxy, 3-hydroxypropyloxy, 2,3-dihydroxypropyloxy,
4-hydroxybutyloxy, 3,4-dihydroxybutyloxy,
1,1-dimethyl-2-hydroxyethyloxy, 5-hydroxypentyloxy,
6-hydroxyhexyloxy, 3,3-dimethyl-3-hydroxypropyloxy,
2-methyl-3-hydroxypropyloxy, 2,3,4-trihydroxybutyloxy,
perhydroxyhexyloxy, etc.
Examples of oxiranyl lower alkoxy groups include C.sub.1-6
straight- or branched-chain alkoxy groups having 1 or 2 oxyranyl
groups such as, for example, oxiranylmethoxy, 2-oxiranylethoxy,
1-oxiranylethoxy, 3-oxiranylpropoxy, 4-oxiranylbutoxy,
5-oxiranylpentyloxy, 6-oxiranylhexyloxy,
1,1-dimethyl-2-oxiranylethoxy, 2-methyl-3-oxiranylpropoxy, etc.
Examples of protecting groups of protected hydroxy groups include
lower alkanoyl and other acyl groups; phenyl (lower)alkyl groups
which may have one or more suitable substituents (e.g., benzyl,
phenethyl, 3-phenylpropyl, 4-methoxybenzyl, trityl, etc.);
trisubstituted silyl groups [e.g., tri(lower)alkylsilyl groups
(e.g., trimethylsilyl, t-butyldimethylsilyl, etc.) and the like];
tetrahydropyranyl; etc.
Examples of nitrogen atom-containing heterocyclic groups include
pyrrolidinyl, imidazolidinyl, piperidyl, hexahydropyrimidinyl,
piperazinyl, octahydroisoindolyl, azepanyl, azocanyl, pyrrolyl,
dihydropyrrolyl, imidazolyl, dihydroimidazolyl, triazolyl,
dihydrotriazolyl, pyrazolyl, pyridyl and N-oxides thereof,
dihydropyridyl, pyrimidinyl, dihydropyrimidinyl, pyrazinyl,
dihydropyrazinyl, pyridazinyl, tetrazolyl, indolyl, isoindolyl,
indolinyl, isoindolinyl, hexahydroisoindolinyl, benzoimidazolyl,
quinolyl, isoquinolyl, indazolyl, quinazolinyl,
dihydroquinazolinyl, benzotriazolyl, carbazolyl, oxazolyl,
isooxazolyl, oxadiazolyl, oxazolidinyl, isooxazolidinyl,
morpholinylbenzoxazolyl, dihydrobenzoxazolyl, benzoxazinyl,
dihydrobenzoxazinyl, benzoxazolyl, benzooxadiazolyl, thiazolyl,
dihydrothiazolyl, isothiazolyl, thiadiazolyl, dihydrothiazinyl,
thiazolyzinyl, benzothiazolyl, benzothiadiazolyl, etc.
Unsubstituted or halogen-substituted lower alkoxy groups are
straight- or branched-chain alkoxy groups having 1 to 6 carbon
atoms, or such alkoxy groups substituted with 1 to 7 halogen atoms.
Examples thereof include methoxy, ethoxy, n-propoxy, isopropoxy,
n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, 1-ethylpropoxy,
n-pentoxy, neopentoxy, n-hexyloxy, isohexyloxy, 3-methylpentoxy,
fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy,
dichloromethoxy, trichloromethoxy, bromomethoxy, dibromomethoxy,
dichlorofluoromethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy,
2,2,2-trifluoroethoxy, pentafluoroethoxy, 2-chloroethoxy,
3,3,3-trifluoropropoxy, heptafluoropropoxy, heptafluoroisopropoxy,
3-chloropropoxy, 2-chloropropoxy, 3-bromopropoxy,
4,4,4-trifluorobutoxy, 4,4,4,3,3-pentafluorobutoxy, 4-chlorobutoxy,
4-bromobutoxy, 2-chlorobutoxy, 5,5,5-trifluoropentoxy,
5-chloropentoxy, 6,6,6-trifluorohexyloxy, 6-chlorohexyloxy,
etc.
Examples of lower alkanoyl groups include formyl, acetyl,
propionyl, butyryl, isobutyryl, pentanoyl, tert-butylcarbonyl,
hexanoyl, and other C.sub.1-6 straight- or branched-chain alkanoyl
groups.
Examples of lower alkylthio groups include methylthio, ethylthio,
n-propylthio, isopropylthio, n-butylthio, tert-butylthio,
n-pentylthio, n-hexylthio, and other C.sub.1-6 straight- or
branched-chain alkylthio groups.
Preferable examples of lower alkylsulfonyl groups include C.sub.1-6
straight- or branched-chain alkylsulfonyl groups. More specific
examples thereof include methylsulfonyl, ethylsulfonyl,
n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl,
isobutylsulfonyl, tert-butylsulfonyl, sec-butylsulfonyl,
n-pentylsulfonyl, isopentylsulfonyl, neopentylsulfonyl,
n-hexylsulfonyl, isohexylsulfonyl, 3-methylpentylsulfonyl, etc.
Lower alkenylene groups include, for example, vinylidene,
propylene, butenylene, and other C.sub.2-6 straight- or
branched-chain alkenylene groups having 1 to 3 double bonds.
Preferable examples of lower alkoxycarbonyl groups include groups
composed of a C.sub.1-6 straight- or branched-chain alkoxy group
and a carbonyl group. Specific examples thereof include
methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl,
isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl,
tert-butoxycarbonyl, sec-butoxycarbonyl, n-pentoxycarbonyl,
neopentoxycarbonyl, n-hexyloxycarbonyl, isohexyloxycarbonyl,
3-methylpentoxycarbonyl, etc.
Lower alkylene groups include, for example, ethylene, trimethylene,
2-methyltrimethylene, 2,2-dimethyltrimethylene,
1-methyltrimethylene, methylmethylene, ethylmethylene,
tetramethylene, pentamethylene, hexamethylene, and other C.sub.1-6
straight- or branched-chain alkylene groups.
Examples of lower alkoxy lower alkoxy groups include alkoxyalkoxy
groups in which the two alkoxy moieties are each independently a
C.sub.1-6 straight- or branched-chain alkoxy group. Specific
examples thereof include methoxymethoxy, 2-methoxyethoxy,
3-methoxypropoxy, 4-methoxybutoxy, 5-methoxypentoxy,
6-methoxyhexyloxy, ethoxymethoxy, 2-ethoxyethoxy, n-propoxymethoxy,
isopropoxymethoxy, n-butoxymethoxy, etc.
Examples of C.sub.1-4 alkylene groups include ethylene,
trimethylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene,
1-methyltrimethylene, methylmethylene, ethylmethylene,
tetramethylene, and other C.sub.1-4 straight- or branched-chain
alkylene groups.
Production Process for Compound Represented by Formula (1)
The oxazole compound represented by Formula (1) can be produced by
various processes, one example of which is shown in Reaction Scheme
1.
##STR00008## wherein R.sup.1, R.sup.2 and W are as defined in
Formula (1), and X is a halogen atom.
Compound (1) is produced by reacting Compound (2) with Compound
(3).
The reaction of Compound (2) with Compound (3) is usually performed
in a suitable solvent. A wide variety of known solvents can be used
as long as they do not inhibit the reaction. Examples of such
solvents include dimethylformamide, dimethylsulfoxide,
acetonitrile, and other aprotic polar solvents; acetone, methyl
ethyl ketone, and other ketone solvents; benzene, toluene, xylene,
tetralin, liquid paraffin, and other hydrocarbon solvents;
methanol, ethanol, isopropanol, n-butanol, tert-butanol, and other
alcohol solvents; tetrahydrofuran, dioxane, dipropyl ether, diethyl
ether, dimethoxyethane, diglyme, and other ether solvents; ethyl
acetate, methyl acetate, and other ester solvents; mixtures
thereof; etc. Such solvents may contain water.
The proportion of Compound (3) to Compound (2) is usually 0.5 to 5
mol, and preferably 0.5 to 3 mol, per mol of Compound (2).
The reaction of Compound (2) with Compound (3) is usually performed
by continuing stirring at -20 to 200.degree. C., and preferably at
0 to 150.degree. C., for 30 minutes to 60 hours, and preferably 1
to 30 hours.
Compound (3) used as a starting material is an easily available
known compound. Compound (2) encompasses novel compounds, and a
production process for such a compound is described hereinafter
(Reaction Scheme 9).
Among the oxazole compounds represented by Formula (1), those in
which W is a divalent group represented by --Y.sup.1-A.sup.1-
wherein Y.sup.1 is --C(.dbd.O)--N(R.sup.3)-- (hereinafter referred
to as "Compound (1a)") can be produced by, for example, the process
shown in Reaction Scheme 2.
##STR00009## wherein R.sup.1, R.sup.2, R.sup.3 and A.sup.1 are as
defined in Formula (1).
Compound (1a) is produced by reacting Compound (4) or a reactive
derivative thereof at the carboxy group, with Compound (5) or a
reactive derivative thereof at the amino or imino group.
Preferable examples of reactive derivatives of Compound (4) include
acid halides, acid anhydrides, activated amides, activated esters,
etc. Preferable examples of reactive derivatives include acid
chlorides; acid azides; dialkylphosphoric acids, phenylphosphoric
acid, diphenylphosphoric acid, dibenzylphosphoric acid, phosphoric
acid halides, and other substituted phosphoric acids,
dialkylphosphorous acid, sulfurous acid, thiosulfuric acid,
sulfuric acid, methanesulfonic acid, and other sulfonic acids,
acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic
acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid,
trichloroacetic acid, and other aliphatic carboxylic acids, and
mixed acid anhydrides with acids such as benzoic acid or other
aromatic acids; symmetrical acid anhydrides; activated amides with
imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or
tetrazole; cyanomethyl ester, methoxymethyl ester,
dimethyliminomethyl ester, vinyl ester, propargyl ester,
p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl
ester, pentachlorophenyl ester, mesylphenyl ester, and other
activated esters, esters with N,N-dimethylhydroxylamine,
1-hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide,
N-hydroxyphthalimide, 1-hydroxy-1H-benzotriazol, and other
N-hydroxy compounds; etc. Such reactive derivatives can be selected
as desired, according to the type of Compound (4) used.
When using Compound (4) in the form of a free acid or a salt
thereof in the above reaction, it is preferable to perform the
reaction in the presence of condensing agent(s). A wide variety of
condensing agents known in this field can be used, including, for
example, N,N'-dicyclohexylcarbodiimide;
N-cyclohexyl-N'-morpholinoethylcarbodiimide;
N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide;
N,N'-diethylcarbodiimide; N,N'-diisopropylcarbodiimide;
N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide and hydrochlorides
thereof; N,N'-carbonylbis(2-methylimidazole);
pentamethyleneketene-N-cyclohexylimine;
diphenylketene-N-cyclohexylimine; ethoxyacetylene,
1-alkoxy-1-chloroethylene; trialkyl phosphite; ethyl polyphosphate;
isopropyl polyphosphate; phosphorus oxychloride (phosphoryl
chloride); phosphorus trichloride; phosphoryl diphenyl azide;
thionyl chloride; oxalyl chloride; ethyl chloroformate, isopropyl
chloroformate, and other lower alkyl haloformates;
triphenylphosphine; 2-ethyl-7-hydroxybenzisooxazolium salt;
2-ethyl-5-(m-sulfophenyl)isooxazolium hydroxide inner salts;
hexafluorophosphoric acid
benzotriazol-1-yloxy-tris(dimethylamino)phosphonium;
1-(p-chlorobenzene-sulfonyloxy)-6-chloro-1H-benzotriazol; so-called
Vilsmeier reagents prepared by reacting N,N-dimethylformamide with
thionyl chloride, phosgene, trichloromethyl chloroformate,
phosphorus oxychloride, etc.; and the like. It is more preferable
to perform the reaction in the presence of such condensing agent(s)
and active esterifying agent(s) such as N-hydroxysuccinimide,
N-hydroxyphthalimide, 1-hydroxy-1H-benzotriazol, or the like.
Preferable examples of reactive derivatives of Compound (5) include
Schiff base imino- or enamine-type tautomers produced by reacting
Compound (5) with carbonyl compounds such as aldehydes, ketones,
etc.; silyl derivatives produced by reacting Compound (5) with
silyl compounds such as bis(trimethylsilyl)acetamide,
mono(trimethylsilyl)acetamide, bis(trimethylsilyl)urea, etc.;
derivatives produced by reacting Compound (5) with phosphorus
trichloride, phosgene, etc.; and the like.
The reaction is usually carried out in a known solvent that does
not adversely affect the reaction. Such solvents include, for
example, water; methanol, ethanol, isopropanol, n-butanol,
trifluoroethanol, ethylene glycol, and other alcohol solvents;
acetone, methyl ethyl ketone, and other ketone solvents;
tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether,
diglyme, and other ether solvents; methyl acetate, ethyl acetate,
and other ester solvents; acetonitrile, N,N-dimethylformamide,
dimethyl sulfoxide, and other aprotic polar solvents; n-pentane,
n-hexane, n-heptane, cyclohexane, and other hydrocarbon solvents;
methylene chloride, ethylene chloride, and other halogenated
hydrocarbon solvents; other organic solvents; and mixed solvents
thereof.
The reaction may be performed in the presence of base(s). A wide
variety of known inorganic and organic bases are usable. Inorganic
bases include, for example, alkali metals (e.g., sodium, potassium,
etc.), alkali metal hydrogencarbonates (e.g., lithium
hydrogencarbonate, sodium hydrogencarbonate, potassium
hydrogencarbonate etc.), alkali metal hydroxides (e.g., lithium
hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide,
etc.), alkali metal carbonates (e.g., lithium carbonate, sodium
carbonate, potassium carbonate, cesium carbonate, etc.), alkali
metal lower alkoxides (e.g., sodium methoxide, sodium ethoxide,
etc.), and alkali metal hydrides (e.g., sodium hydride, potassium
hydride, etc.). Organic bases include, for example, trialkylamines
[e.g., trimethylamine, triethylamine, N-ethyldiisopropylamine,
etc.], pyridine, quinoline, piperidine, imidazole, picoline,
dimethylaminopyridine, dimethylaniline, N-methylmorpholine,
1,5-diazabicyclo[4.3.0]non-5-ene (DBN),
1,4-diazabicyclo[2.2.2]octane (DABCO),
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), etc. When such bases are
liquid, they can also be used as solvents.
Such bases can be used singly or in combination.
The amount of base(s) is usually 0.1 to 10 moles, and preferably
0.1 to 3 moles, per mole of Compound (4).
The proportion of Compound (4) to Compound (5) in Reaction Scheme 1
is usually at least 1, and preferably about 1 to about 5 mol of the
former per mol of the latter.
The reaction temperature is not limited, and the reaction can
usually be performed with cooling, at room temperature, or with
heating. It is suitable to perform the reaction in a temperature
range from room temperature to 100.degree. C., for 30 minutes to 30
hours, and preferably for 30 minutes to 5 hours.
In the above reaction, Compound (4) for use as a starting material
is an easily available known compound. Compound (5) encompasses
novel compounds. A production process for Compound (5) is described
hereinafter (Reaction Scheme 10).
Among the oxazole compounds represented by Formula (1), those in
which W is a divalent group represented by --Y.sup.1-A.sup.1-
wherein Y.sup.1 is --C(.dbd.O)-- and A.sup.1 is a lower alkylene
group having one lower alkoxycarbonyl group (hereinafter referred
to as "Compound (1b)") can be produced, for example, by the process
shown in Reaction Scheme 3.
##STR00010## wherein R.sup.1 and R.sup.2 are as defined in Formula
(1), R.sup.7 and R.sup.8 are each independently a lower alkyl
group, and A.sup.1a is a C.sub.1-5 alkylene group.
The --COOR.sup.8 group in Formula (1b) is the same as the lower
alkoxycarbonyl group defined as a substituent of A.sup.1 in Formula
(1). The lower alkyl group represented by R.sup.7 may be the same
as the lower alkyl group as defined above.
Examples of the C.sub.1-5 alkylene group represented by A.sup.1a
include ethylene, trimethylene, 2-methyltrimethylene,
2,2-dimethyltrimethylene, 1-methyltrimethylene, methylmethylene,
ethylmethylene, tetramethylene, pentamethylene, and other C.sub.1-5
straight- or branched-chain alkylene groups.
Compound (1b) is produced by reacting Compound (6) with Compound
(7).
The reaction is usually performed in a known solvent that does not
adversely affect the reaction. Such solvents include, for example,
water; methanol, ethanol, isopropanol, n-butanol, trifluoroethanol,
ethylene glycol, and other alcohol solvents; acetone, methyl ethyl
ketone, and other ketone solvents; tetrahydrofuran, dioxane,
diethyl ether, dimethoxyethane, diglyme, and other ether solvents;
methyl acetate, ethyl acetate, and other ester solvents;
acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide,
N-methylpyrrolidone, and other aprotic polar solvents; methylene
chloride, ethylene chloride, and other halogenated hydrocarbon
solvents; other organic solvents; and mixed solvents thereof.
The reaction can usually be performed in the presence of suitable
base(s). A wide variety of known inorganic and organic bases are
usable. Inorganic bases include, for example, alkali metals (e.g.,
lithium, sodium, potassium, etc.), alkali metal hydrogencarbonates
(e.g., lithium hydrogencarbonate, sodium hydrogencarbonate,
potassium hydrogencarbonate, etc.), alkali metal hydroxides (e.g.,
lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium
hydroxide, etc.), alkali metal carbonates (e.g., lithium carbonate,
sodium carbonate, potassium carbonate, cesium carbonate, etc.),
alkali metal lower alkoxides (e.g., sodium methoxide, sodium
ethoxide, potassium tert-butoxide, sodium tert-butoxide, sodium
tert-pentoxide, etc.), alkali metal hydrides (e.g., sodium hydride,
potassium hydride, etc.), and the like. Organic bases include, for
example, trialkylamines (e.g., trimethylamine, triethylamine,
N-ethyldiisopropylamine, etc.), pyridine, quinoline, piperidine,
imidazole, picoline, dimethylaminopyridine, dimethylaniline,
N-methylmorpholine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN),
1,4-diazabicyclo[2.2.2]octane (DABCO),
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), etc. When such bases are
liquid, they can also be used as solvents. Such bases can be used
singly or in combination.
The amount of base(s) is usually 0.5 to 10 mol, and preferably 0.5
to 6 mol, per mol of Compound (6).
The proportion of Compound (6) to Compound (7) is usually at least
1 mol, and preferably about 1 to about 5 mol of the former, per mol
of the latter.
The reaction temperature is not limited, and the reaction can
usually be performed with cooling, at room temperature, or with
heating. It is suitable to perform the reaction in a temperature
range from room temperature to 150.degree. C., for 30 minutes to 60
hours, and preferably 1 to 30 minutes.
Compound (6) used as a starting material in the above reaction is
an easily available known compound. Compound (7) encompasses novel
compounds. A production process for Compound (7) is described
hereinafter (Reaction Scheme 11).
Among the oxazole compounds represented by Formula (1), those in
which W is a divalent group represented by --Y.sup.1-A.sup.1-
wherein A.sup.1 is a lower alkylene group (hereinafter referred to
as "Compound (1d)") are produced from the corresponding compounds
in which A.sup.l is a lower alkylene group having lower
alkoxycarbonyl group(s) (hereinafter referred to as "Compound
(1c)"), by the process shown in Reaction Scheme 4.
##STR00011## wherein R.sup.1, R.sup.2 and Y.sup.1 are as defined in
Formula (1), A.sup.1b is a lower alkylene group having lower
alkoxycarbonyl group(s), and A.sup.1c is a lower alkylene
group.
Compound (1d) is produced by subjecting Compound (1c) to
hydrolysis-decarboxylation.
The reaction is usually performed in a known solvent that does not
adversely affect the reaction. Such solvents include, for example,
water; methanol, ethanol, isopropanol, n-butanol, trifluoroethanol,
ethylene glycol, and other alcohol solvents; acetone, methyl ethyl
ketone, and other ketone solvents; tetrahydrofuran, dioxane,
diethyl ether, dimethoxyethane, diglyme, and other ether solvents;
methyl acetate, ethyl acetate, and other ester solvents;
acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide,
N-methylpyrrolidone, and other aprotic polar solvents; methylene
chloride, ethylene chloride, and other halogenated hydrocarbon
solvents; other organic solvents; and mixed solvents thereof.
The hydrolysis-decarboxylation of Compound (1c) is usually
performed under acidic conditions. For example, an acid is added to
a suspension or solution of Compound (1c) in a suitable solvent,
and the resulting mixture is stirred at 0 to 120.degree. C. to
carry out the hydrolysis-decarboxylation.
Examples of usable acids include trifluoroacetic acid, acetic acid,
and other organic acids, hydrochloric acid, bromic acid,
hydrobromic acid, sulfuric acid, and other inorganic acids, etc.
Among such organic acids, organic acids can also be used as
reaction solvents.
The amount of acid(s) is usually 0.5 to 30 mol, and preferably 0.5
to 10 mol, per mol of Compound (1c).
The reaction temperature is usually 0 to 120.degree. C., and
preferably room temperature to 110.degree. C. The reaction time is
usually 30 minutes to 24 hours, preferably 30 minutes to 12 hours,
and more preferably 1 to 8 hours.
Among the oxazole compounds represented by Formula (1), those in
which R.sup.1 is a phenyl group substituted on the phenyl ring with
hydroxy group(s) (hereinafter referred to as "Compound (1f)") are
produced from the corresponding compounds in which R.sup.1 is a
phenyl group substituted on the phenyl ring with protected hydroxy
group(s) (hereinafter referred to as "Compound (1e)"), by the
process shown in Reaction Scheme 5.
##STR00012## wherein R.sup.2 and W are as defined in Formula (1);
R.sup.9 is a protected hydroxy group; R.sup.10 is the same group as
the substituent (1-2), (1-3), (1-4), (1-5), (1-6), (1-7), (1-8),
(1-9) or (1-10) of the aryl group represented by R.sup.1 in Formula
(1); m is 1 to 5; q is 0 to 4; m R.sup.9s may be the same or
different; and q R.sup.10s may be the same or different; with the
proviso that m+q.ltoreq.5.
Compound (1f) can be produced by subjecting Compound (1e) to an
elimination reaction of the hydroxy protecting group(s).
The elimination reaction can be carried out by hydrolysis,
hydrogenolysis, or other conventional methods.
The reaction is usually performed in a known solvent that does not
adversely affect the reaction. Such solvents include, for example,
water; methanol, ethanol, isopropanol, n-butanol, trifluoroethanol,
ethylene glycol, and other alcohol solvents; acetone, methyl ethyl
ketone, and other ketone solvents; tetrahydrofuran, dioxane,
diethyl ether, dimethoxyethane, diglyme, and other ether solvents;
methyl acetate, ethyl acetate, and other ester solvents;
acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide,
N-methylpyrrolidone, and other aprotic polar solvents; methylene
chloride, ethylene chloride, and other halogenated hydrocarbon
solvents; and other organic solvents.
(i) Hydrolysis:
Hydrolysis is preferably carried out in the presence of base(s) or
acid(s) (including Lewis acids).
A wide variety of known inorganic and organic bases are usable.
Preferable examples of inorganic bases include alkali metals (e.g.,
sodium, potassium, etc.), alkaline earth metals (e.g., magnesium,
calcium, etc.), hydroxides, carbonates and hydrogencarbonates
thereof, etc. Preferable examples of organic bases include
trialkylamines (e.g., trimethylamine, triethylamine, etc.),
picoline, 1,5-diazabicyclo[4,3,0]non-5-ene, etc.
A wide variety of known organic and inorganic acids are usable.
Preferable organic acids include, for example, formic acid, acetic
acid, propionic acid, and other fatty acids; trichloroacetic acid,
trifluoroacetic acid, and other trihaloacetic acids; and the like.
Preferable inorganic acids include, for example, hydrochloric acid,
hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen
bromide, etc. Examples of Lewis acids include boron trifluoride
ether complexes, boron tribromide, aluminium chloride, ferric
chloride, etc.
When using a trihaloacetic acid or Lewis acid, it is preferable to
carry out hydrolysis in the presence of a cation scavenger (e.g.,
anisole, phenol, etc.).
The amount of base(s) or acid(s) is not limited as long as it is an
amount necessary for hydrolysis.
The reaction temperature is usually 0 to 120.degree. C., preferably
room temperature to 100.degree. C., and more preferably room
temperature to 80.degree. C. The reaction time is usually 30
minutes to 24 hours, preferably 30 minutes to 12 hours, and more
preferably 1 to 8 hours.
(ii) Hydrogenolysis:
Hydrogenolysis can be carried out by a wide variety of known
methods including, for example, chemical reduction, catalytic
reduction, etc.
Examples of suitable reducing agents for chemical reduction include
hydrides (e.g., hydrogen iodide, hydrogen sulfide, lithium
aluminium hydride, sodium borohydride, sodium cyanoborohydride,
etc.); and combinations of metals (e.g., tin, zinc, iron, etc.) or
metallic compounds (e.g., chromium chloride, chromium acetate,
etc.), with organic or inorganic acids (e.g., formic acid, acetic
acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid,
hydrochloric acid, hydrobromic acid, etc.).
Examples of suitable catalysts for catalytic reduction include
platinum catalysts (e.g., platinum plates, spongy platinum,
platinum black, colloidal platinum, platinum oxide, platinum wires,
etc.), palladium catalysts (e.g., spongy palladium, palladium
black, palladium oxide, palladium carbon, palladium/barium sulfate,
palladium/barium carbonate, etc.), nickel catalysts (e.g., reduced
nickel, nickel oxide, Raney nickel, etc.), cobalt catalysts (e.g.,
reduced cobalt, Raney cobalt, etc.), iron catalysts (e.g., reduced
iron and the like), etc.
When such acids used for chemical reduction are liquid, they can
also be used as solvents.
The amounts of reducing agent for chemical reduction and catalyst
for catalytic reduction are not limited and may be conventional
amounts.
The reaction temperature is usually 0 to 120.degree. C., preferably
room temperature to 100.degree. C., and more preferably room
temperature to 80.degree. C. The reaction time is usually 30
minutes to 24 hours, preferably 30 minutes to 10 hours, and more
preferably 30 minutes to 4 hours.
Among the oxazole compounds represented by Formula (1), those in
which R.sup.1 is a phenyl group substituted on the phenyl ring with
R.sup.11O-- group(s) (hereinafter referred to as "Compound (1 g)")
are produced from Compound (1f), by the process shown in Reaction
Scheme 6.
##STR00013## wherein R.sup.2 and W are as defined in Formula (1);
R.sup.10, m and q are as defined above; X.sup.1 is a halogen atom
or a group that undergoes the same substitution reaction as that of
a halogen atom; R.sup.11O is the same group as the substituent
(1-2), (1-3), (1-4), (1-5), (1-6), (1-7), (1-8), (1-9) or (1-10) of
the aryl group represented by R.sup.1 in Formula (1); and m
R.sup.11Os may be the same or different.
In Compound (8), the halogen atom represented by X.sup.1 is a
fluorine atom, chlorine atom, bromine atom, or iodine atom.
Examples of the group that undergoes the same substitution reaction
as that of a halogen atom, the group being represented by X.sup.1,
include lower alkanesulfonyloxy groups, arylsulfonyloxy groups,
aralkylsulfonyloxy groups, etc.
Specific examples of lower alkanesulfonyloxy groups include
methanesulfonyloxy, ethanesulfonyloxy, isopropanesulfonyloxy,
n-propanesulfonyloxy, n-butanesulfonyloxy, tert-butanesulfonyloxy,
n-pentanesulfonyloxy, n-hexanesulfonyloxy, and other C.sub.1-6
straight- or branched-chain alkanesulfonyloxy groups, and the
like.
Arylsulfonyloxy groups include, for example, phenylsulfonyloxy,
naphthylsulfonyloxy, etc. The phenyl ring of such arylsulfonyloxy
groups may have, for example, 1 to 3 substituents selected from the
group consisting of C.sub.1-6 straight- or branched-chain alkyl
groups, C.sub.1-6 straight- or branched-chain alkoxy groups, nitro
groups, and halogen atoms. Specific examples of such
arylsulfonyloxy groups include phenylsulfonyloxy,
4-methylphenylsulfonyloxy, 2-methylphenylsulfonyloxy,
4-nitrophenylsulfonyloxy, 4-methoxyphenylsulfonyloxy,
2-nitrophenylsulfonyloxy, 3-chlorophenylsulfonyloxy, etc. Specific
examples of naphthylsulfonyloxy groups include
.alpha.-naphthylsulfonyloxy, .beta.-naphthylsulfonyloxy, etc.
Aralkylsulfonyloxy groups include, for example, phenyl-substituted
C.sub.1-6 straight- or branched-chain alkylsulfonyloxy groups which
may have, on the phenyl ring, 1 to 3 substituents selected from the
group consisting of C.sub.1-6 straight- or branched-chain alkyl
groups, C.sub.1-6 straight- or branched-chain alkoxy groups, nitro
groups, and halogen atoms; naphthyl-substituted C.sub.1-6 straight-
or branched-chain alkylsulfonyloxy groups; etc. Specific examples
of phenyl-substituted alkylsulfonyloxy groups as mentioned above
include benzylsulfonyloxy, 2-phenylethylsulfonyloxy,
4-phenylbutylsulfonyloxy, 2-methylbenzylsulfonyloxy,
4-methoxybenzylsulfonyloxy, 4-nitrobenzylsulfonyloxy,
3-chlorobenzylsulfonyloxy, etc. Specific examples of
naphthyl-substituted alkylsulfonyloxy groups as mentioned above
include .alpha.-naphthylmethylsulfonyloxy,
.beta.-naphthylmethylsulfonyloxy, etc.
Compound (1 g) is produced by reacting Compound (1f) with Compound
(8), or by reacting Compound (1f) with Compound (8').
The reaction of Compound (1f) with Compound (8) is described
below.
The reaction of Compound (1f) with Compound (8) is usually
performed in a known solvent that does adversely affect the
reaction. Such solvents include, for example, water; methanol,
ethanol, isopropanol, n-butanol, trifluoroethanol, ethylene glycol,
and other alcohol solvents; acetone, methyl ethyl ketone, and other
ketone solvents; tetrahydrofuran, dioxane, diethyl ether, diglyme,
and other ether solvents; methyl acetate, ethyl acetate, and other
ester solvents; acetonitrile, N,N-dimethylformamide, dimethyl
sulfoxide, and other aprotic polar solvents; methylene chloride,
ethylene chloride, and other halogenated hydrocarbon solvents;
other organic solvents; mixed solvents thereof; etc.
The reaction of Compound (1f) with Compound (8) is usually carried
out in the presence of base(s). Usable bases include known
inorganic and organic bases. Inorganic bases include, for example,
alkali metals (e.g., sodium, potassium, etc.), alkali metal
hydrogencarbonates (e.g., lithium hydrogencarbonate, sodium
hydrogencarbonate, potassium hydrogencarbonate, etc.), alkali metal
hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassium
hydroxide, cesium hydroxide, etc.), alkali metal carbonates (e.g.,
lithium carbonate, sodium carbonate, potassium carbonate, cesium
carbonate, etc.), alkali metal lower alkoxides (e.g., sodium
methoxide, sodium ethoxide, etc.), alkali metal hydrides (e.g.,
sodium hydride, potassium hydride, etc.), and the like. Organic
bases include, for example, trialkylamines (e.g., trimethylamine,
triethylamine, N-ethyldiisopropylamine, etc.), pyridine, quinoline,
piperidine, imidazole, picoline, dimethylaminopyridine,
dimethylaniline, N-methylmorpholine,
1,5-diazabicyclo[4.3.0]non-5-ene (DBN),
1,4-diazabicyclo[2.2.2]octane (DABCO),
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), etc. When such bases are
liquid, they can also be used as solvents. Such bases can be used
singly or in combination.
The amount of base(s) is usually 0.5 to 10 mol, and preferably 0.5
to 6 mol, per mol of Compound (1f).
When performing the above reaction, alkali metals such as potassium
iodide, sodium iodide, etc. can be added as reaction accelerators
to the reaction system, as required.
The proportion of Compound (1f) to Compound (8) is usually at least
1 mol, and preferably about 1 to about 5 mol of the latter, per mol
of the former.
The reaction temperature is not limited, and the reaction can
usually be performed with cooling, at room temperature, or with
heating. It is suitable to perform the reaction at about room
temperature for 1 to 30 hours.
Next, the reaction of Compound (1f) with Compound (8') is
described.
The reaction of Compound (1f) with Compound (8') is usually
performed in a known solvent that does not adversely affect the
reaction. Such solvents include, for example, water; methanol,
ethanol, isopropanol, n-butanol, trifluoroethanol, ethylene glycol,
and other alcohol solvents; acetone, methyl ethyl ketone, and other
ketone solvents; tetrahydrofuran, dioxane, diethyl ether, diglyme,
and other ether solvents; methyl acetate, ethyl acetate, and other
ester solvents; acetonitrile, N,N-dimethylformamide, dimethyl
sulfoxide, and other aprotic polar solvents; benzene, toluene,
xylene, and other aromatic hydrocarbon solvents; methylene
chloride, ethylene chloride, and other halogenated hydrocarbon
solvents; other organic solvents; mixed solvents thereof; etc.
The reaction is usually performed in the presence of dialkyl
azodicarboxylate(s) such as diisopropyl azodicarboxylate, diethyl
azodicarboxylate, etc., and phosphine ligand(s) such as triphenyl
phosphine, tri(n-butyl)phosphine, etc. The amount of dialkyl
azodicarboxylate(s) is usually 0.5 to 10 mol, and preferably 0.5 to
6 mol, per mole of Compound (1f). The amount of phosphine ligand(s)
is usually 0.5 to 10 mol, and preferably 0.5 to 6 mol, per mole of
Compound (1f).
The reaction of Compound (1f) with Compound (8') can be carried out
in the presence of suitable base(s). A wide variety of known
inorganic and organic bases are usable. Inorganic bases include,
for example, alkali metals (e.g., sodium, potassium, etc.), alkali
metal hydrogencarbonates (e.g., lithium hydrogencarbonate, sodium
hydrogencarbonate, potassium hydrogencarbonate, etc.), alkali metal
hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassium
hydroxide, cesium hydroxide, etc.), alkali metal carbonates (e.g.,
lithium carbonate, sodium carbonate, potassium carbonate, cesium
carbonate, etc.), alkali metal lower alkoxides (e.g., sodium
methoxide, sodium ethoxide, etc.), alkali metal hydrides (e.g.,
sodium hydride, potassium hydride, etc.), and the like. Organic
bases include, for example, trialkylamines (e.g., trimethylamine,
triethylamine, N-ethyldiisopropylamine, etc.), pyridine, quinoline,
piperidine, imidazole, picoline, dimethylaminopyridine,
dimethylaniline, N-methylmorpholine,
1,5-diazabicyclo[4.3.0]non-5-ene (DBN),
1,4-diazabicyclo[2.2.2]octane (DABCO),
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), etc. When such bases are
liquid, they can also be used as solvents. Such bases can be used
singly or in combination.
The amount of base(s) is usually 0.5 to 10 mol, and preferably 0.5
to 6 mol, per mol of Compound (1f).
The proportion of Compound (1f) to Compound (8') is usually at
least 1 mol, and preferably about 1 to about 5 mol of the latter,
per mol of the former.
The reaction temperature is not limited, and the reaction can
usually be performed with cooling, at room temperature, or with
heating. It is suitable to perform the reaction at about room
temperature for 1 to 30 hours.
Compounds (8) and (8') used as starting materials in the above
reaction are easily available known compounds.
Among the oxazole compounds represented by Formula (1), those in
which W is a divalent group represented by --Y.sup.1-A.sup.1-
wherein Y.sup.1 is --C(.dbd.O) and A.sup.1 is a lower alkenylene
group (hereinafter referred to as "Compound (1h)") can be produced
by, for example, the process shown in Reaction Scheme 7.
##STR00014## wherein R.sup.1 and R.sup.2 are as defined in Formula
(1), and A.sup.1d is a C.sub.2-4 alkenylene group, a C.sub.1-4
alkylene group, or a direct bond.
Each of the C.sub.2-4 alkenyl group and C.sub.1-4 alkylene group
may be straight- or branched-chain. --CH.dbd.CH-A.sup.1d
corresponds to the lower alkenylene group represented by A.sup.1 in
Formula (1).
Compound (1h) is produced by reacting Compound (9) with Compound
(10).
The reaction is usually performed in a known solvent that does not
adversely affect the reaction. Such solvents include, for example,
water; methanol, ethanol, isopropanol, n-butanol, trifluoroethanol,
ethylene glycol, and other alcohol solvents; acetone, methyl ethyl
ketone, and other ketone solvents; tetrahydrofuran, dioxane,
diethyl ether, dimethoxyethane, diglyme, and other ether solvents;
methyl acetate, ethyl acetate, and other ester solvents;
acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide,
N-methylpyrrolidone, and other aprotic polar solvents; methylene
chloride, ethylene chloride, and other halogenated hydrocarbon
solvents; other organic solvents; mixed solvents thereof; etc.
The reaction can be performed in the presence of base(s). A wide
variety of known inorganic and organic bases are usable. Inorganic
bases include, for example, alkali metals (e.g., lithium, sodium,
potassium, etc.), alkali metal hydrogencarbonates (e.g., lithium
hydrogencarbonate, sodium hydrogencarbonate, potassium
hydrogencarbonate, etc.), alkali metal hydroxides (e.g., lithium
hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide,
etc.), alkali metal carbonates (e.g., lithium carbonate, sodium
carbonate, potassium carbonate, cesium carbonate, etc.), alkali
metal lower alkoxides (e.g., sodium methoxide, sodium ethoxide,
potassium tert-butoxide, sodium tert-butoxide, etc.), alkali metal
hydrides (e.g., sodium hydride, potassium hydride, etc.), and the
like. Organic bases include, for example, trialkylamines (e.g.,
trimethylamine, triethylamine, N-ethyldiisopropylamine, etc.),
pyridine, quinoline, piperidine, imidazole, picoline,
dimethylaminopyridine, dimethylaniline, N-methylmorpholine,
1,5-diazabicyclo[4.3.0]non-5-ene (DBN),
1,4-diazabicyclo[2.2.2]octane (DABCO),
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), etc. When such bases are
liquid, they can also be used as solvents. Such bases can be used
singly or in combination.
The amount of base(s) is usually 0.5 to 10 mol, and preferably 0.5
to 6 mol, per mol of Compound (9).
The proportion of Compound (9) to Compound (10) is usually at least
1 mol, and preferably about 1 to about 5 mol of the latter, per mol
of the former.
The reaction temperature is not limited, and the reaction can
usually be performed with cooling, at room temperature, or with
heating. It is suitable to perform the reaction in a temperature
range from room temperature to 150.degree. C., for 30 minutes to 60
hours, and preferably for 1 to 30 hours.
Compound (9) used as a starting material in the above reaction is
an easily available known compound. Compound (10) used as a
starting material in the above reaction can be produced by the
process shown in Reaction Scheme 12.
Among the oxazole compounds represented by Formula (1), those in
which W is a divalent group represented by --Y.sup.1-A.sup.1-
wherein A.sup.1 is a lower alkylene group (hereinafter referred to
as "Compound (1j)") can be produced from compounds in which A.sup.1
is a lower alkenylene group (hereinafter referred to as "Compound
(1i)"), by the process shown in Reaction Scheme 8.
##STR00015## wherein R.sup.1 and R.sup.2 are as defined in Formula
(1), Y.sup.1 is as defined above, A.sup.1e is a lower alkenylene
group, and A.sup.1f is a lower alkylene group.
Compound (1j) is produced by subjecting Compound (1i) to
hydrogenolysis.
The reaction is performed under the same reaction conditions as of
the reaction shown in Reaction Scheme 5 for the hydrogenolysis of
Compound (1e) to obtain Compound (1f). Therefore, the same
reagent(s) and reaction conditions (e.g., solvent, reaction
temperature, etc.) as those used in the hydrogenolysis shown in
Reaction Scheme 5 can be used in the above reaction.
##STR00016## wherein R.sup.2 and W are as defined in Formula (1),
and X is as defined above.
The halogenation reaction of Compound (11) is performed in a
suitable solvent in the presence of a halogenating agent. Usable
halogenating agents include, for example, Br.sub.2, Cl.sub.2, and
other halogen molecules; iodine chloride, sulfuryl chloride, cupric
bromide, and other copper compounds; N-bromosuccinimide,
N-chlorosuccinimide, and other N-halosuccinimides, etc. Usable
solvents include, for example, dichloromethane, dichloroethane,
chloroform, carbon tetrachloride, and other halogenated
hydrocarbons; acetic acid, propionic acid, and other fatty acids;
carbon disulfide; etc. The amount of halogenating agent is usually
1 to 10 mol, and preferably 1 to 5 mol, per mol of Compound (11).
The reaction is usually complete at 0.degree. C. to the boiling
point temperature of the solvent, and preferably about 0 to about
100.degree. C., in about 5 minutes to about 20 hours.
Among Compounds (5) for use as starting materials, those in which
R.sup.3 is a hydrogen atom (hereinafter referred to as "Compound
(5a)") are produced by the process shown in Reaction Scheme 10.
##STR00017## wherein R.sup.1 and A.sup.1 are as defined in Formula
(1), X.sup.2 and X.sup.3 are each independently a halogen atom or a
group that undergoes the same substitution reaction as that of a
halogen atom as mentioned above, and M is an alkali metal.
Examples of the alkali metal represented by M include sodium,
potassium, etc.
Compound (14) is produced by reacting Compound (12) with Compound
(13).
The reaction of Compound (12) with Compound (13) is usually
performed in a known solvent that does not adversely affect the
reaction. Such solvents include, for example, water; methanol,
ethanol, isopropanol, n-butanol, trifluoroethanol, ethylene glycol,
and other alcohol solvents; acetone, methyl ethyl ketone, and other
ketone solvents; tetrahydrofuran, dioxane, diethyl ether,
dimethoxyethane, diglyme, and other ether solvents; methyl acetate,
ethyl acetate, and other ester solvents; acetonitrile,
N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, and
other aprotic polar solvents; methylene chloride, ethylene
chloride, and other halogenated hydrocarbon solvents; and other
organic solvents; etc.
The proportion of Compound (12) to Compound (13) is usually at
least 1 mol, and preferably about 1 to about 5 mol of the latter,
per mol of the former. The reaction of Compound (12) with Compound
(13) is performed by continuing stirring usually in a temperature
range from room temperature to 200.degree. C., and preferably from
room temperature to 150.degree. C., usually for 30 minutes to 60
hours, and preferably 1 to 30 hours.
Compound (16) is produced by reacting Compound (15) with Compound
(14).
The reaction of Compound (15) with Compound (14) is usually
performed in a known solvent that does not adversely affect the
reaction. Such solvents include, for example, water; methanol,
ethanol, isopropanol, n-butanol, trifluoroethanol, ethylene glycol,
and other alcohol solvents; acetone, methyl ethyl ketone, and other
ketone solvents; tetrahydrofuran, dioxane, diethyl ether, diglyme,
and other ether solvents; methyl acetate, ethyl acetate, and other
ester solvents; acetonitrile, N,N-dimethylformamide, dimethyl
sulfoxide, and other aprotic polar solvents; methylene chloride,
ethylene chloride, and other halogenated hydrocarbon solvents;
other organic solvents; mixtures thereof; etc.
When performing the reaction of Compound (15) with Compound (14),
alkali metal iodides such as potassium iodide, sodium iodide, etc.
can be added as reaction accelerators to the reaction system, as
required.
The proportion of Compound (15) to Compound (14) is usually at
least 1 mol, and preferably about 1 to about 5 mol of the latter,
per mol of the former.
The temperature of the reaction of Compound (15) with Compound (14)
is not limited, and the reaction can usually be performed with
cooling, at room temperature, or with heating. It is suitable to
perform the reaction in a temperature range from room temperature
to 100.degree. C., for 1 to 60 hours, and preferably for 1 to 30
hours.
In the reaction of Compound (15) with Compound (14), phthalimide
can be used in place of Compound (15) and the reaction may be
performed in the presence of base(s). A wide variety of known
inorganic and organic bases are usable. Examples of inorganic bases
include alkali metals (e.g., lithium, sodium, potassium, etc.),
alkali metal hydrogencarbonates (e.g., lithium hydrogencarbonate,
sodium hydrogencarbonate, potassium hydrogencarbonate, etc.),
alkali metal hydroxides (e.g., lithium hydroxide, sodium hydroxide,
potassium hydroxide, cesium hydroxide, etc.), alkali metal
carbonates (e.g., lithium carbonate, sodium carbonate, potassium
carbonate, cesium carbonate, etc.), alkali metal lower alkoxides
(e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide,
sodium tert-butoxide, etc.), alkali metal hydrides (e.g., sodium
hydride, potassium hydride, etc.), and the like. Organic bases
include, for example, trialkylamines (e.g., trimethylamine,
triethylamine, N-ethyldiisopropylamine, etc.), pyridine, quinoline,
piperidine, imidazole, picoline, dimethylaminopyridine,
dimethylaniline, N-methylmorpholine,
1,5-diazabicyclo[4.3.0]non-5-ene (DBN),
1,4-diazabicyclo[2.2.2]octane (DABCO),
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), etc.
The amount of base(s) is usually 0.5 to 10 mol, and preferably 0.5
to 6 mol, per mol of Compound (14).
Compound (5a) is produced by reacting Compound (16) with Compound
(17).
The reaction of Compound (16) with Compound (17) is usually
performed in a known solvent that does not adversely affect the
reaction. Such solvents include, for example, water; methanol,
ethanol, isopropanol, n-butanol, trifluoroethanol, ethylene glycol,
and other alcohol solvents; acetone, methyl ethyl ketone, and other
ketone solvents; tetrahydrofuran, dioxane, diethyl ether, diglyme,
and other ether solvents; methyl acetate, ethyl acetate, and other
ester solvents; acetonitrile, N,N-dimethylformamide, dimethyl
sulfoxide, and other aprotic polar solvents; methylene chloride,
ethylene chloride, and other halogenated hydrocarbon solvents;
other organic solvents; mixtures thereof; etc.
The proportion of Compound (16) to Compound (17) is usually at
least 1 mol, and preferably about 1 to about 5 mol of the latter,
per mol of the former.
The temperature of the reaction of Compound (16) with Compound (17)
is not limited, and the reaction can usually be performed with
cooling, at room temperature, or with heating. It is suitable to
perform the reaction at about room temperature for 1 to 30
hours.
##STR00018## wherein R.sup.1 is as defined in Formula (1); R.sup.8
and A.sup.1a are as defined above; X.sup.4 is a halogen atom or a
group that undergoes the same substitution reaction as that of a
halogen atom as mentioned above; and R.sup.12 is a lower alkyl
group.
Compound (20) is produced by reacting Compound (18) with Compound
(19).
The reaction of Compound (18) with Compound (19) is usually
performed in a known solvent that does not adversely affect the
reaction. Such solvents include, for example, water; methanol,
ethanol, isopropanol, n-butanol, trifluoroethanol, ethylene glycol,
and other alcohol solvents; acetone, methyl ethyl ketone, and other
ketone solvents; tetrahydrofuran, dioxane, diethyl ether,
dimethoxyethane, diglyme, and other ether solvents; methyl acetate,
ethyl acetate, and other ester solvents; acetonitrile,
N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, and
other aprotic polar solvents; methylene chloride, ethylene
chloride, and other halogenated hydrocarbon solvents; other organic
solvents; mixtures thereof; etc.
The reaction of Compound (18) with Compound (19) can usually be
performed in the presence of suitable base (s). A wide variety of
known inorganic and organic bases are usable. Inorganic bases
include, for example, alkali metals (e.g., lithium, sodium,
potassium, etc.), alkali metal hydrogencarbonates (e.g., lithium
hydrogencarbonate, sodium hydrogencarbonate, potassium
hydrogencarbonate, etc.), alkali metal hydroxides (e.g., lithium
hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide,
etc.), alkali metal carbonates (e.g., lithium carbonate, sodium
carbonate, potassium carbonate, cesium carbonate, etc.), alkali
metal lower alkoxides (e.g., sodium methoxide, sodium ethoxide,
potassium tert-butoxide, sodium tert-butoxide, etc.), alkali metal
hydrides (e.g., sodium hydride, potassium hydride, etc.), and the
like. Organic bases include, for example, trialkylamines (e.g.,
trimethylamine, triethylamine, N-ethyldiisopropylamine, etc.),
pyridine, quinoline, piperidine, imidazole, picoline,
dimethylaminopyridine, dimethylaniline, N-methylmorpholine,
1,5-diazabicyclo[4.3.0]non-5-ene (DBN),
1,4-diazabicyclo[2.2.2]octane (DABCO),
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), etc. When such bases are
liquid, they can also be used as solvents.
Such bases can be used singly or in combination.
The amount of base(s) is usually 0.5 to 10 mol, and preferably 0.5
to 6 mol, per mol of Compound (18).
The proportion of Compound (18) to Compound (19) in Reaction Scheme
11 is usually at least 1 mol, and preferably about 1 to about 5 mol
of the latter, per mol of the former.
The reaction temperature is not limited, and the reaction can
usually be performed with cooling, at room temperature, or with
heating. It is suitable to perform the reaction in a temperature
range from room temperature to 100.degree. C., for 30 minutes to 60
hours, and preferably 1 to 30 hours.
Compound (7) is produced by subjecting Compound (20) to
hydrolysis-decarboxylation. The hydrolysis-decarboxylation of
Compound (20) can be carried out by the process shown in Reference
Example 48 given hereinafter, a process similar thereto, the
process shown in Reaction Scheme 4 above, or a process similar
thereto.
##STR00019## wherein R.sup.1 is as defined in Formula (1), and
X.sup.2 and Aid are as defined above.
Compound (10) is produced by subjecting Compound (21) to an
oxidation reaction. The reaction can be carried out by the process
shown in Reference Example 64 given hereinafter, or a process
similar thereto, and is performed in the presence of a known
solvent that does not adversely affect the reaction. Such solvents
include, for example, water; methanol, ethanol, isopropanol,
n-butanol, trifluoroethanol, ethylene glycol, and other alcohol
solvents; acetone, methyl ethyl ketone, and other ketone solvents;
tetrahydrofuran, dioxane, diethyl ether, diglyme, and other ether
solvents; methyl acetate, ethyl acetate, and other ester solvents;
acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, and other
aprotic polar solvents; methylene chloride, ethylene chloride, and
other halogenated hydrocarbon solvents; other organic solvents;
mixtures thereof; etc.
The reaction is usually performed using oxidizing agent(s) such as
dimethyl sulfoxide, hexamethylenetetramine, triethylamine-N-oxide,
etc.
If necessary, the reaction can be performed in the presence of
suitable base(s). A wide variety of known inorganic and organic
bases are usable. Inorganic bases include, for example, alkali
metals (e.g., sodium, potassium, etc.), alkali metal
hydrogencarbonates (e.g., lithium hydrogencarbonate, sodium
hydrogencarbonate, potassium hydrogencarbonate, etc.), alkali metal
hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassium
hydroxide, cesium hydroxide, etc.), alkali metal carbonates (e.g.,
lithium carbonate, sodium carbonate, potassium carbonate, cesium
carbonate, etc.), alkali metal lower alkoxides (e.g., sodium
methoxide, sodium ethoxide, etc.), alkali metal hydrides (e.g.,
sodium hydride, potassium hydride, etc.), and the like. Organic
bases include, for example, trialkylamines (e.g., trimethylamine,
triethylamine, N-ethyldiisopropylamine, etc.), pyridine, quinoline,
piperidine, imidazole, picoline, dimethylaminopyridine,
dimethylaniline, N-methylmorpholine,
1,5-diazabicyclo[4.3.0]non-5-ene (DBN),
1,4-diazabicyclo[2.2.2]octane (DABCO),
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), etc. When such bases are
liquid, they can also be used as solvents. Such bases can be used
singly or in combination.
The amount of oxidizing agent is usually 0.5 to 10 mol, and
preferably 0.5 to 6 mol, per mol of Compound (21).
The amount of base(s) is usually 0.5 to 10 mol, and preferably 0.5
to 6 mol, per mol of Compound (21).
When performing the above reaction, alkali metals such as potassium
iodide, sodium iodide, etc. can be added as reaction accelerators
to the reaction system, as required.
The reaction temperature is not limited, and the reaction can
usually be performed with cooling, at room temperature, or with
heating. It is suitable to perform the reaction in a temperature
range from room temperature to 120.degree. C. for 30 minutes to 30
hours.
The starting material compounds used in the above reaction schemes
may be suitable salts, and the objective compounds obtained by the
above reactions may be in the form of suitable salts.
Each of the objective compounds obtained according to the above
reaction schemes can be isolated and purified from the reaction
mixture by, for example, cooling the reaction mixture, separating
the crude reaction product from the reaction mixture by an
isolation procedure such as filtration, concentration, extraction
and/or other isolation procedures, and then purifying the crude
reaction product by column chromatography, recrystallization and/or
other conventional purification procedures.
Suitable salts of Compound (1) are pharmaceutically acceptable
salts including, for example, metal salts such as alkali metal
salts (e.g., sodium salt, potassium salt, etc.), alkaline earth
metal salts (e.g., calcium salt, magnesium salt, etc.), etc.,
ammonium salts, alkali metal carbonates (e.g., lithium carbonate,
potassium carbonate, sodium carbonate, cesium carbonate, etc.),
alkali metal hydrogencarbonates (e.g., lithium hydrogencarbonate,
sodium hydrogencarbonate, potassium hydrogencarbonate, etc.),
alkali metal hydroxides (e.g., lithium hydroxide, sodium hydroxide,
potassium hydroxide, cesium hydroxide, etc.), and other salts of
inorganic bases; tri(lower)alkylamines (e.g., trimethylamine,
triethylamine, N-ethyldiisopropylamine, etc.), pyridine, quinoline,
piperidine, imidazole, picoline, dimethylaminopyridine,
dimethylaniline, N-(lower)alkylmorpholines (e.g.,
N-methylmorpholine and the like), DBN, DBU, DABCO, and other salts
of organic bases; hydrochlorides, hydrobrmides, hydroiodides,
sulfates, nitrates, phosphates, and other salts of inorganic acids;
formates, acetates, propionates, oxalates, malonates, succinates,
fumarates, maleates, lactates, malates, citrates, tartrates,
citrates, carbonates, picrates, methanesulfonates,
ethanesulfonates, p-toluenesulfonates, glutamates, and other salts
of inorganic acids; etc.
The starting material compounds and objective compounds represented
by the formulae in the above reaction schemes encompass solvates
(e.g. hydrates, ethanolates, etc.). Preferable solvates include
hydrates.
The compounds represented by Formula (1) of the present invention
of course encompass isomers such as geometrical isomers,
stereoisomer, optical isomers, etc.
Drug Efficacy and Use
Compounds represented by formula (1), optically active isomers
thereof, and salts thereof (hereinafter referred to as "compounds
of the present invention") have a specific inhibitory action
against PDE4, and are hence useful as active ingredients for a PDE4
inhibitor.
Further, due to their PDE4-specific inhibitory action, the
compounds of the invention can be useful as active ingredients of
pharmaceutical compositions used as prophylactic and therapeutic
agents for various diseases. More specifically, diseases
efficiently preventable and treatable by the PED4-specific
inhibitory action include various origin-generated acute and
chronic (in particular, inflammatory and allergen induced)
respiratory tract diseases (e.g. bronchial asthma, chronic
obstructive pulmonary disease, etc.); dermatoses (in particular,
hyperplastic, inflammatory, and allergic diseases) (e.g. psoriasis
(vulgaris), toxic and allergic contact eczema, atopic dermatitis,
alopecia areata, and other hyperplastic, inflammatory and allergic
dermatoses); nervous function abnormality diseases such as
learning, memory, and/or cognition disorders associated with
Altzheimer's and Perkinson's diseases; diseases associated with
mental function abnormality (e.g. manic-depressive psychosis,
schizophrenia, anxiety disorder, etc.); systemic and local
arthritic disorders (e.g. knee osteoarthritis, articular
rheumatism, etc.); gastrointestinal diffuse inflammation (e.g.
Crohn's disease and ulcerative colitis); allergic and/or chronic
immune-mediated inflammatory diseases in the upper respiratory
tract (cavum pharynges, nose) and its vicinity (sinuses, eyes)
(e.g. allergic rhinitis/sinusitis, chronic rhinitis/sinusitis,
allergic conjunctivitis), and the like. Among these, the compounds
are particularly effective in preventing and treating atopic
dermatitis, making this diseases a suitable target disease for
prevention and treatment.
When used as a PDE4 inhibitor or as prophylactic or therapeutic
agent for the above-mentioned various diseases, the compounds of
the invention can be used as oral agents, injectable solutions,
external preparations, and the like.
For oral agents, for example, the compounds may be prepared in any
forms such as powders, tablets, granules, capsules, syrups, films,
troches, liquids, etc. Such oral agents can contain
pharmaceutically acceptable base materials and carriers, and
further optionally contain as necessary binders, disintegrators,
lubricants, humectants, buffers, preservatives, fragrances, and the
like.
For injectable solutions, the compounds may be prepared in the form
of solutions dissolved in physiological saline, grape sugar
solutions and the like, or aqueous suspensions.
For external preparations, the compounds may be prepared in any
forms, for example, such as liquid medicines, oily medicines,
lotions, liniments, emulsions, suspensions, creams, ointments, etc.
Such external preparations can optionally contain various carriers,
base materials, and additives as typically used in external
preparations, and examples include water, oils, surfactants,
solubilized components, emulsifiers, colorants (dyes and pigments),
fragrances, preservatives, disinfectants, thickeners, antioxidants,
chelators, pH adjusting agents, deodorants, etc.
When used as a PDE4 inhibitor, or as prophylactic or therapeutic
agent for the aforementioned various diseases, effective dose and
number of doses a day of the compound vary depending on the purpose
of use, kind of compound used, the age, weight, symptoms, etc. of a
subject, and cannot be uniformly prescribed. For example, the
inhibitor or agent can be administered in a dose of 0.1 to 1000 mg
of the compound(s) of the present invention per day per adult, and
may be administered in one to several portions a day.
Further, in light of other viewpoints, the present invention
provides a method for treating or preventing the aforementioned
various diseases comprising the step of administrating an effective
dose of the compound(s) of the invention to a mammal, such as a
human.
Furthermore, since the compounds of the present invention have
inhibitory action against TNF-.alpha. production, they are useful
as active ingredients for TNF-.alpha. production suppressants.
Diseases that benefit from such TNF-.alpha. production inhibitory
action include those efficiently preventable and treatable by the
aforementioned PDE4-specific inhibitory action. Preparation forms,
administration routes and doses of TNF-.alpha. production
suppressant containing compounds of the invention are the same as
those of the aforementioned PDE4 inhibitor and prophylactic and
therapeutic agents.
EFFECT OF THE INVENTION
The compounds of the present invention have an inhibitory action
specific against PDE4, and are hence useful as active ingredients
for a PDE 4 inhibitors.
Due to their specific PDE4 inhibitory activity, the compounds of
the invention are further useful as prophylactic and therapeutic
agents for various diseases including atopic dermatitis.
BEST MODE FOR CARRYING OUT THE INVENTION
The present invention is described in more detail below with
reference to Examples; however, the present invention is not
limited thereto.
Reference Example 1
A 25 g quantity of isovanillic acid was suspended in 250 ml of
methanol, and 1.5 g of p-toluenesulfonic acid monohydrate was
added. The mixture was heated and refluxed overnight. After
completion of the reaction, methanol was distilled off under
reduced pressure. The residue was neutralized with saturated
aqueous sodium bicarbonate and then extracted with ethyl acetate.
After washing with saturated brine twice, the organic layer was
separated and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (n-hexane:ethyl
acetate=1:1) to give 24.5 g of white crystalline methyl
3-hydroxy-4-methoxybenzoate.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.63-7.58 (2H, m), 6.67 (1H, d,
J=8.1 Hz), 5.63 (1H, s), 3.98 (3H, s), 3.90 (3H, s)
Reference Example 2
A 20 g quantity of methyl 3-hydroxy-4-methoxybenzoate obtained in
Reference Example 1 was dissolved in 200 ml of methanol, and 24.6
ml of 1,8-diazabicyclo[5,4,0]undec-7-ene and 21 g of benzyl bromide
were added. The mixture was heated and refluxed overnight. After
the reaction mixture was concentrated, water was added to the
residue and extraction with ethyl acetate was performed. The
extract was washed with saturated brine twice, and the organic
layer was separated and dried over magnesium sulfate. After
insolubles were removed by filtration, the filtrate was
concentrated under reduced pressure to give 25.5 g of white
crystalline methyl 3-benzyloxy-4-methoxybenzoate.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.68 (1H, dd, J=8.4, 1.8 Hz),
7.61 (1H, d, J=1.8 Hz), 7.48-7.28 (5H, m), 6.91 (1H, d, J=8.4 Hz),
5.17 (2H, s), 3.93 (3H, s), 3.87 (3H, s)
Reference Example 3
A 25 g quantity of the methyl 3-benzyloxy-4-methoxybenzoate
obtained in Reference Example 2 was dissolved in 100 ml of
acetonitrile, and a solution of 11 g of sodium hydroxide in 100 ml
of water was added. The mixture was stirred with heating at
40.degree. C. for 5 hours. The reaction mixture was cooled with
ice, and concentrated hydrochloric acid was added to give a pH of
about 3. The precipitated crystals were collected by filtration and
dried under reduced pressure to give 22.1 g of white crystalline
3-benzyloxy-4-methoxybenzoic acid.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.77 (1H, dd, J=8.4, 1.8 Hz),
7.65 (1H, d, J=1.8 Hz), 7.48-7.29 (5H, m), 6.94 (1H, d, J=8.4 Hz),
5.19 (2H, s), 3.95 (3H, s)
Reference Example 4
A 20 g quantity of the 3-benzyloxy-4-methoxybenzoic acid obtained
in Reference Example 3 was suspended in 200 ml of dichloromethane,
and one drop of dimethylformamide was added. A 8.1 ml quantity of
oxalyl chloride was added dropwise with ice-cooling and stirring.
After 2 hours, the reaction mixture was concentrated under reduced
pressure. The residue was dissolved in 50 ml of tetrahydrofuran and
the resulting solution was added dropwise to 28% aqueous ammonia
with ice-cooling and stirring. The obtained mixture was stirred for
1 hour and the precipitated crystals were collected by filtration
and dried under reduced pressure to give 19.9 g of white powdery
3-benzyloxy-4-methoxybenzamide.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.85-7.28 (7H, m), 6.90 (1H, d,
J=8.1 Hz), 5.67 (2H, br s), 5.18 (2H, s), 3.93 (3H, s)
Reference Example 5
A 15 g quantity of 3-benzyloxy-4-methoxybenzamide obtained in
Reference Example 4 was suspended in 450 ml of isopropanol, and
13.9 g of 1,3-dichloro-2-propanone was added. The mixture was
heated and refluxed overnight. After the reaction mixture was
concentrated to half its original volume under reduced pressure,
200 ml of n-hexane was added to the concentrate and the mixture was
stirred. The precipitated crystals were collected by filtration and
dried under reduced pressure to give 12.2 g of white powdery
2-(3-benzyloxy-4-methoxyphenyl)-4-chloromethyl oxazole.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.73-7.71 (3H, m), 7.50-7.29 (5H,
m), 6.95 (1H, d, J=5.7 Hz), 5.20 (2H, s), 4.56 (2H, s), 3.93 (3H,
s)
Reference Example 6
A 11 g quantity of 2-(3-benzyloxy-4-methoxyphenyl)-4-chloromethyl
oxazole obtained in Reference Example 5 was suspended in 220 ml of
ethanol, and 7.5 g of sodium iodide and 9.3 g of potassium
phthalimide were added. The mixture was heated and refluxed
overnight. The reaction mixture was cooled with ice, and the
precipitated crystals were collected by filtration. The obtained
crude crystals were suspended and washed with 100 ml of water. The
resulting crystals were dried under reduced pressure to give 9.4 g
of white powdery
2-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]isoindolin-1,3-dione.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.91-7.85 (2H, m) 7.76-7.69 (2H,
m), 7.61-7.58 (3H, m) 7.46 (2H, d, J=6.6 Hz), 7.39-7.26 (3H, m),
6.91 (1H, d, J=9 Hz), 5.18 (2H, s), 4.85 (2H, s), 3.90 (3H, s)
Reference Example 7
A 9 g quantity of the
2-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]isoindolin-1,3-dione
obtained in Reference Example 6 was suspended in 200 ml of ethanol,
and 3.1 ml of hydrazine monohydrate was added. The mixture was
heated and refluxed for 3 hours. After cooing the reaction mixture,
200 ml of dichloromethane was added and the mixture was stirred.
Insolubles were removed by filtration, and the filtrate was
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (NH silica, product of Fuji
Sylisia Chemical Ltd., dichloromethane:methanol=20:1) to give 4.5 g
of pale yellow powdery
[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-yl]methylamine.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.63-7.59 (2H, m) 7.53-7.46 (3H,
m), 7.41-7.27 (3H, m) 6.94 (1H, d, J=9 Hz), 5.20 (2H, s), 3.89 (3H,
s), 3.87 (2H, s), 2.14 (2H, br s)
Reference Example 8
A 15 g quantity of methyl 3-hydroxy-4-methoxybenzoate obtained in
Reference Example 1 was dissolved in 150 ml of dimethylformamide,
and 34 g of potassium carbonate and 22.2 g of
(bromomethyl)cyclopropane were added. The mixture was heated at
90.degree. C. overnight. Ice water was added to the reaction
mixture, and the precipitated crystals were collected by filtration
and washed with an excess of water. The obtained crystals were
dried under reduced pressure at room temperature to give 18.3 g of
white crystalline methyl
3-cyclopropylmethoxy-4-methoxybenzoate.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.67 (1H, dd, J=8.4, 1.8 Hz),
7.52 (1H, d, J=2.1 Hz), 6.89 (1H, d, J=8.4 Hz), 3.94-3.86 (8H, m),
1.43-1.29 (1H, m), 0.70-0.58 (2H, m), 0.45-0.30 (2H, m)
Reference Example 9
Using 18 g of methyl 3-cyclopropylmethoxy-4-methoxybenzoate
obtained in Reference Example 8 and following the procedure of
Reference Example 3, 16.6 g of white crystalline
3-cyclopropylmethoxy-4-methoxybenzoic acid was obtained.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.76 (1H, dd, J=8.4, 1.8 Hz),
7.58 (1H, d, J=2.1 Hz), 6.92 (1H, d, J=8.4 Hz), 3.98-3.92 (8H, m),
1.43-1.29 (1H, m), 0.70-0.58 (2H, m), 0.46-0.35 (2H, m)
Reference Example 10
Using 16.5 g of 3-cyclopropylmethoxy-4-methoxybenzoic acid obtained
in Reference Example 9 and following the procedure of Reference
Example 4, 16.2 g of pale yellow powdery
3-cyclopropylmethoxy-4-methoxybenzamide was obtained.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.43 (1H, d, J=2.1 Hz), 7.31 (1H,
dd, J=8.4, 2.1 Hz), 6.88 (1H, d, J=8.1 Hz), 5.75 (2H, br s),
3.97-3.89 (5H, m), 1.40-1.28 (1H, m), 0.69-0.62 (2H, m), 0.39-0.33
(2H, m)
Reference Example 11
Using 13 g of 3-cyclopropylmethoxy-4-methoxybenzamide obtained in
Reference Example 10 and following the procedure of Reference
Example 5, 10.5 g of pale yellow powdery
4-chloromethyl-2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazole was
obtained.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.65 (1H, d, J=0.9 Hz), 7.20 (1H,
dd, J=8.7, 2.1 Hz), 7.53 (1H, d, J=2.1 Hz), 6.93 (1H, d, J=8.4 Hz),
4.57 (2H, s), 3.97-3.90 (5H, m), 1.43-1.32 (1H, m), 0.71-0.63 (2H,
m), 0.41-0.35 (2H, m)
Reference Example 12
Using 8 g of
4-chloromethyl-2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazole
obtained in Reference Example 11 and following the procedure of
Reference Example 6, 10 g of white crystalline
2-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]isoindolin-1-
,3-dione was obtained.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.90-7.84 (2H, m), 7.76-7.69 (2H,
m), 7.62 (1H, s), 7.57 (1H, dd, J=8.4, 2.1 Hz), 7.48 (1H, d, J=2.1
Hz), 6.89 (1H, d, J=8.4 Hz), 4.85 (2H, s), 3.95-3.90 (5H, m),
1.41-1.31 (1H, m), 0.69-0.62 (2H, m), 0.41-0.35 (2H, m)
Reference Example 13
Using 9.5 g of
2-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]isoindolin-1-
,3-dione obtained in Reference Example 12 and following the
procedure of Reference Example 7, 5.1 g of white powdery
[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-yl]methylamine
was obtained.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.61-7.55 (1H, m), 7.53-7.50 (2H,
m), 6.92 (1H, d, J=8.4 Hz), 3.96-3.87 (5H, m), 3.83 (2H, s),
1.41-1.33 (1H, m), 0.70-0.63 (2H, m), 0.41-0.35 (2H, m)
Reference Example 14
A 5 g quantity of methyl 3-hydroxy-4-methoxybenzoate obtained in
Reference Example 1 was dissolved in 100 ml of dimethylformamide,
and 11.3 g of potassium carbonate and 5.64 g of isobutyl bromide
were added. The mixture was heated at 80.degree. C. for 6 hours.
Ice water was added to the reaction mixture, and the precipitated
crystals were collected by filtration and washed with an excess of
water. The resulting crystals were dried under reduced pressure at
room temperature to give 5.85 g of white powdery methyl
3-isobutoxy-4-methoxybenzoate.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.65 (1H, dd, J=8.4, 2.1 Hz),
7.53 (1H, d, J=1.8 Hz), 6.88 (1H, d, J=8.1 Hz), 3.96 (3H, s), 3.91
(3H, s), 3.82 (2H, d, J=6.9 Hz), 2.20-2.11 (1H, m), 1.05 (6H, d,
J=6.6 Hz)
Reference Example 15
Using 5.85 g of methyl 3-isobutoxy-4-methoxybenzoate obtained in
Reference Example 14 and following the procedure of Reference
Example 3, 5.6 g of white powdery 3-isobutoxy-4-methoxybenzoic acid
was obtained.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.75 (1H, dd, J=8.4, 1.8 Hz),
7.58 (1H, d, J=2.1 Hz), 6.91 (1H, d, J=8.7 Hz), 3.94 (3H, s), 3.83
(2H, d, J=6.6 Hz), 2.26-2.12 (1H, m), 1.05 (6H, d, J=6.6 Hz)
Reference Example 16
Using 5.5 g of 3-isobutoxy-4-methoxybenzoic acid obtained in
Reference Example 15 and following the procedure of Reference
Example 4, 5.1 g of pale yellow powdery
3-isobutoxy-4-methoxybenzamide was obtained.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.43 (1H, d, J=2.1 Hz), 7.31 (1H,
dd, J=8.4, 2.1 Hz), 6.87 (1H, d, J=8.7 Hz), 5.78 (2H, br s), 3.91
(3H, s), 3.83 (2H, d, J=6.6 Hz), 2.25-2.11 (1H, m), 1.04 (6H, d,
J=6.6 Hz)
Reference Example 17
Using 5 g of 3-isobutoxy-4-methoxybenzamide obtained in Reference
Example 16 and following the procedure of Reference Example 5, 3.4
g of pale yellow powdery
4-chloromethyl-2-(3-isobutoxy-4-methoxyphenyl)oxazole was
obtained.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.65 (1H, s), 7.60 (1H, dd,
J=8.4, 2.1 Hz), 7.53 (1H, d, J=2.1 Hz), 6.92 (1H, d, J=8.4 Hz),
4.57 (2H, s), 3.91 (3H, s), 3.85 (2H, d, J=6.9 Hz), 2.27-2.13 (1H,
m), 1.05 (6H, d, J=6.6 Hz)
Reference Example 18
Using 3.3 g of
4-chloromethyl-2-(3-isobutoxy-4-methoxyphenyl)oxazole obtained in
Reference Example 17 and following the procedure of Reference
Example 6, 4.4 g of white powdery
2-[2-(3-isobutoxy-4-methoxyphenyl)oxazol-4-ylmethyl]isoindolin-1,3-dione
was obtained.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.91-7.84 (2H, m), 7.76-7.71 (2H,
m), 7.62 (1H, s), 7.55 (1H, dd, J=8.4, 2.1 Hz), 7.49 (1H, d, J=2.1
Hz), 6.88 (1H, d, J=8.4 Hz), 4.85 (2H, s), 3.89 (3H, s), 3.83 (2H,
d, J=6.6 Hz), 2.23-2.13 (1H, m), 1.05 (6H, d, J=6.6 Hz)
Reference Example 19
Using 4.4 g of
2-[2-(3-isobutoxy-4-methoxyphenyl)oxazol-4-ylmethyl]isoindolin-1,3-dione
obtained in Reference Example 18 and following the procedure of
Reference Example 7, 2 g of white solid
[2-(3-isobutoxy-4-methoxyphenyl)oxazol-4-yl]methylamine was
obtained.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.60-7.51 (3H, m), 6.92 (1H, d,
J=8.4 Hz), 3.91 (3H, s), 3.87-3.84 (4H, m), 2.27-2.13 (1H, m), 1.71
(2H, br s), 1.06 (6H, d, J=6.6 Hz)
Reference Example 20
Using 10 g of methyl 3-hydroxy-4-methoxybenzoate obtained in
Reference Example 1 and following the procedure of Reference
Example 14, 12.5 g of white powdery methyl
4-methoxy-3-(2,2,2-trifluoroethoxy)benzoate was obtained.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.79 (1H, dd, J=8.7, 1.8 Hz),
7.63 (1H, s), 6.94 (1H, d, J=8.7 Hz), 4.42 (2H, q, J=8.1 Hz), 3.94
(3H, s), 3.91 (3H, s)
Reference Example 21
Using 12 g of methyl 4-methoxy-3-(2,2,2-trifluoro ethoxy)benzoate
obtained in Reference Example 20 and following the procedure of
Reference Example 3, 11.5 g of white powdery
4-methoxy-3-(2,2,2-trifluoroethoxy)benzoic acid was obtained.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.86 (1H, dd, J=8.4, 1.8 Hz),
7.67 (1H, d, J=1.8 Hz), 6.97 (1H, d, J=8.4 Hz), 4.43 (2H, q, J=8.4
Hz), 3.96 (3H, s)
Reference Example 22
Using 11.5 g of 4-methoxy-3-(2,2,2-trifluoroethoxy)benzoic acid
obtained in Reference Example 21 and following the procedure of
Reference Example 4, 10.8 g of white powdery
4-methoxy-3-(2,2,2-trifluoroethoxy)benzamide was obtained.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.50 (1H, br s), 7.49 (1H, dd,
J=8.4, 2.4 Hz), 6.94 (1H, d, J=8.4 Hz), 4.43 (2H, q, J=8.4 Hz),
3.93 (3H, s)
Reference Example 23
Using 10.5 g of 4-methoxy-3-(2,2,2-trifluoroethoxy)benzamide
obtained in Reference Example 22 and following the procedure of
Reference Example 5, 7.1 g of pale yellow powdery
4-chloromethyl-2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazole
was obtained.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.75 (1H, dd, J=8.4, 2.1 Hz),
7.66 (1H, br s), 7.64 (1H, d, J=2.1 Hz), 6.98 (1H, d, J=8.4 Hz),
4.56 (2H, s), 4.45 (2H, q, J=8.4 Hz), 3.94 (3H, s)
Reference Example 24
Using 3 g of
4-chloromethyl-2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazole
obtained in Reference Example 23 and following the procedure of
Reference Example 6, 3.6 g of white powdery
2-{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-ylmethyl}isoindo-
lin-1,3-dione was obtained.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.91-7.85 (2H, m), 7.76-7.64 (3H,
m), 7.60 (1H, s), 7.59 (1H, d, J=2.1 Hz), 6.94 (1H, d, J=8.7 Hz),
4.85 (2H, s), 4.43 (2H, q, J=8.4 Hz), 3.91 (3H, s)
Reference Example 25
Using 3.6 g of 2-{2-[4-methoxy-3-(2,2,2-trifluoro
ethoxy)phenyl]oxazol-4-ylmethyl}isoindolin-1,3-dione obtained in
Reference Example 24 and following the procedure of Reference
Example 7, 1.93 g of white powdery
{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-yl}methylamine
was obtained.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.73 (1H, dd, J=8.4, 2.1 Hz),
7.63 (1H, d, J=2.1 Hz), 7.52 (1H, s), 6.98 (1H, d, J=8.4 Hz), 4.46
(2H, q, J=8.4 Hz), 3.93 (3H, s), 3.83 (2H, s), 1.55 (2H, br s)
Reference Example 26
Using 9.5 g of ethyl vanillate and following the procedure of
Reference Example 14, 11 g of white powdery ethyl
3-methoxy-4-(2,2,2-trifluoroethoxy)benzoate was obtained.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.65 (1H, dd, J=8.4, 2.1 Hz),
7.60 (1H, d, J=2.1 Hz), 6.96 (1H, d, J=8.4 Hz), 4.49-4.33 (4H, m),
3.93 (3H, s), 1.39 (3H, t, J=6.9 Hz)
Reference Example 27
A 12 g quantity of ethyl
3-methoxy-4-(2,2,2-trifluoroethoxy)benzoate obtained in Reference
Example 26 was suspended in 120 ml of 47% hydrobromic acid, and the
suspension was heated and refluxed overnight. The reaction mixture
was poured into ice water, and the precipitated crystals were
collected by filtration, washed with an excess of water, and then
dried under reduced pressure to give 8.4 g of pale red powdery
3-hydroxy-4-(2,2,2-trifluoroethoxy)benzoic acid.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.71-7.66 (2H, m), 6.91 (1H, d,
J=5.1 Hz), 5.55 (1H, br s), 4.50 (2H, q, J=7.8 Hz)
Reference Example 28
An 8.4 g quantity of 3-hydroxy-4-(2,2,2-trifluoro ethoxy)benzoic
acid obtained in Reference Example 27 was suspended in 150 ml of
ethanol, and 0.5 ml of concentrated sulfuric acid was added. The
mixture was heated and refluxed overnight. After completion of the
reaction, ethanol was distilled off under reduced pressure. The
residue was neutralized with saturated aqueous sodium bicarbonate
and then extracted with ethyl acetate. After washing with saturated
brine twice, the organic layer was separated and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (n-hexane:ethyl acetate=1:1) to give 7.2 g of white
crystalline ethyl 3-hydroxy-4-(2,2,2-trifluoroethoxy)benzoate.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.66-7.60 (2H, m), 6.87 (1H, d,
J=8.1 Hz), 5.54 (1H, s), 4.48 (2H, q, J=7.8 Hz), 4.35 (2H, q, J=7.2
Hz), 1.38 (3H, t, J=7.2 Hz)
Reference Example 29
Using 7 g of ethyl 3-hydroxy-4-(2,2,2-trifluoro ethoxy)benzoate
obtained in Reference Example 28 and following the procedure of
Reference Example 14, 8.5 g of white powdery ethyl
3-cyclopropylmethoxy-4-(2,2,2-trifluoroethoxy)benzoate was
obtained.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.63 (1H, dd, J=8.7, 2.1 Hz),
7.58 (1H, d, J=2.1 Hz), 7.00 (1H, d, J=8.7 Hz), 4.48 (2H, q, J=8.1
Hz), 4.35 (2H, q, J=6.9 Hz), 3.92 (2H, d, J=7.2 Hz), 1.41-1.25 (4H,
m), 0.69-0.60 (2H, m), 0.40-0.32 (2H, m)
Reference Example 30
Using 8.5 g of ethyl
3-cyclopropylmethoxy-4-(2,2,2-trifluoroethoxy)benzoate obtained in
Reference Example 29 and following the procedure of Reference
Example 3, 7.5 g of white powdery
3-cyclopropylmethoxy-4-(2,2,2-trifluoroethoxy)benzoic acid was
obtained.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.71 (1H, dd, J=8.4, 1.8 Hz),
7.63 (1H, d, J=2.1 Hz), 7.02 (1H, d, J=8.1 Hz), 4.51 (2H, q, J=8.1
Hz), 3.93 (2H, d, J=7.2 Hz), 1.37-1.25 (1H, m), 0.69-0.60 (2H, m),
0.41-0.35 (2H, m)
Reference Example 31
Using 7 g of 3-cyclopropylmethoxy-4-(2,2,2-trifluoroethoxy)benzoic
acid obtained in Reference Example 30 and following the procedure
of Reference Example 4, 7.35 g of white solid
3-cyclopropylmethoxy-4-(2,2,2-trifluoroethoxy)benzamide was
obtained.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.48 (1H, d, J=2.1 Hz), 7.28-7.25
(1H, m), 7.01 (1H, d, J=8.4 Hz), 4.48 (2H, q, J=8.4 Hz), 3.93 (2H,
d, J=6.9 Hz), 1.37-1.25 (1H, m), 0.69-0.60 (2H, m), 0.41-0.35 (2H,
m)
Reference Example 32
Using 5 g of
3-cyclopropylmethoxy-4-(2,2,2-trifluoroethoxy)benzamide obtained in
Reference Example 31 and following the procedure of Reference
Example 5, 3.1 g of white powdery
4-chloromethyl-2-[3-cyclopropylmethoxy-4-(2,2,2-trifluoroethoxy)phenyl]ox-
azole was obtained.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.67 (1H, s), 7.59-7.56 (2H, m),
7.05 (1H, d, J=9.0 Hz), 4.56 (2H, s), 4.48 (2H, q, J=8.4 Hz),
1.35-1.26 (1H, m), 0.70-0.63 (2H, m), 0.41-0.35 (2H, m)
Reference Example 33
Using 0.85 g of
4-chloromethyl-2-[3-cyclopropylmethoxy-4-(2,2,2-trifluoroethoxy)phenyl]ox-
azole obtained in Reference Example 32 and following the procedure
of Reference Example 6, 0.6 g of white powdery
2-{2-[3-cyclopropylmethoxy-4-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-ylmet-
hyl}isoindolin-1,3-dione was obtained.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.91-7.84 (2H, m), 7.76-7.69 (2H,
m), 7.64 (1H, s), 7.60-7.51 (2H, m), 7.01 (1H, d, J=8.7 Hz), 4.85
(2H, s), 4.46 (2H, q, J=8.4 Hz), 3.93 (2H, d, J=6.9 Hz), 1.35-1.24
(1H, m), 0.68-0.61 (2H, m), 0.40-0.34 (2H, m)
Reference Example 34
Using 0.55 g of
2-{2-[3-cyclopropylmethoxy-4-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-ylmet-
hyl}isoindolin-1,3-dione obtained in Reference Example 33 and
following the procedure of Reference Example 7, 0.32 g of white
powdery {2-[3-cyclopropyl
methoxy-4-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-yl}methylamine was
obtained.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.61-7.52 (3H, m), 7.05 (1H, d,
J=8.7 Hz), 4.48 (2H, q, J=8.4 Hz), 3.95 (2H, d, J=7.2 Hz), 3.84
(2H, s), 1.56 (2H, br s), 1.35-1.24 (1H, m), 0.70-0.61 (2H, m),
0.41-0.35 (2H, m)
Reference Example 35
Using 20 g of 3,4-diethoxybenzamide and following the procedure of
Reference Example 5, 24.5 g of white powdery
4-chloromethyl-2-(3,4-diethoxyphenyl)oxazole was obtained.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.65 (1H, s), 7.58 (1H, dd,
J=8.4, 1.8 Hz), 7.54 (1H, d, J=1.8 Hz), 6.92 (1H, d, J=8.4 Hz),
4.56 (2H, s), 4.18 (2H, q, J=6.9 Hz), 4.15 (2H, q, J=6.9 Hz), 1.48
(6H, t, J=6.9 Hz)
Reference Example 36
Using 8 g of 4-chloromethyl-2-(3,4-diethoxyphenyl)oxazole obtained
in Reference Example 35 and following the procedure of Reference
Example 6, 10 g of white powdery
2-[2-(3,4-diethoxyphenyl)oxazol-4-ylmethyl]isoindolin-1,3-dione was
obtained.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.88 (2H, m), 7.72 (2H, m), 7.62
(1H, s), 7.54 (1H, d, J=8.4, 2.1 Hz), 7.50 (1H, d, J=2.1 Hz), 6.88
(1H, d, J=8.4 Hz), 4.85 (2H, s), 4.16 (2H, q, J=6.9 Hz), 4.11 (2H,
q, J=6.9 Hz), 1.47 (6H, t, J=6.9 Hz)
Reference Example 37
Using 10 g of
2-[2-(3,4-diethoxyphenyl)oxazol-4-ylmethyl]isoindolin-1,3-dione
obtained in Reference Example 36 and following the procedure of
Reference Example 7, 5.7 g of white powdery
[2-(3,4-diethoxyphenyl)oxazol-4-yl]methylamine was obtained.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.56 (1H, d, J=8.4, 1.8 Hz), 7.54
(1H, d, J=1.8 Hz), 7.51 (1H, s), 6.91 (1H, d, J=8.4 Hz), 4.18 (2H,
q, J=6.9 Hz), 4.14 (2H, q, J=6.9 Hz), 1.80 (1H, br s), 3.84 (2H,
s), 1.48 (3H, t, J=6.9 Hz), 1.48 (3H, t, J=6.9 Hz)
Reference Example 38
Using 2.0 g of 3,4-dimethoxybenzamide and following the procedure
of Reference Example 5, 2.4 g of white powdery
4-chloromethyl-2-(3,4-dimethoxyphenyl)oxazole was obtained.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.66 (1H, s), 7.62 (1H, dd,
J=8.4, 1.8 Hz), 7.55 (1H, d, J=1.8 Hz), 6.93 (1H, d, J=8.4 Hz),
4.52 (2H, s), 3.95 (3H, s), 3.91 (3H, s)
Reference Example 39
Using 2.4 g of 4-chloromethyl-2-(3,4-dimethoxyphenyl)oxazole
obtained in Reference Example 38 and following the procedure of
Reference Example 6, 2.3 g of white powdery
2-[2-(3,4-dimethoxyphenyl)oxazol-4-ylmethyl]isoindolin-1,3-dione
was obtained.
Reference Example 40
Using 2.3 g of the
2-[2-(3,4-dimethoxyphenyl)oxazol-4-ylmethyl]isoindolin-1,3-dione
obtained in Reference Example 39 and following the procedure of
Reference Example 7, 1.3 g of white powdery
[2-(3,4-dimethoxyphenyl)oxazol-4-yl]methylamine was obtained.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.60 (1H, d, J=8.1, 2.1 Hz), 7.54
(1H, d, J=2.1 Hz), 6.92 (1H, d, J=8.1 Hz), 3.96 (3H, s), 3.93 (3H,
s), 3.85 (2H, s), 1.81 (2H, br s)
Reference Example 41
A 9 g quantity of 4-difluoromethoxy-3-hydroxy benzaldehyde was
dissolved in 180 ml of acetonitrile, and 13.1 g of potassium
carbonate and 8.6 ml of benzyl bromide were added. The mixture was
stirred at room temperature for 4 hours. After insolubles were
removed by filtration, the filtrate was concentrated and the
residue was purified by silica gel column chromatography
(n-hexane:ethyl acetate=1:1) to give 11.9 g of colorless oily
3-benzyloxy-4-difluoromethoxybenzaldehyde.
.sup.1H-NMR (CDCl.sub.3) .delta.: 10.21 (1H, s), 7.56 (1H, t,
J=74.1 Hz), 7.53-7.28 (7H, m), 6.68 (1H, d, J=8.4 Hz), 5.20 (2H,
s)
Reference Example 42
A 6 g quantity of 3-benzyloxy-4-difluoromethoxybenzaldehyde
obtained in Reference Example 41 was dissolved in 500 ml of
acetone, and 17 g of potassium permanganate was added. The mixture
was heated and refluxed overnight. After distilling off acetone
from the reaction mixture, 100 ml of 5N sodium hydroxide was added
to the residue, and insolubles were removed by filtration.
Concentrated hydrochloric acid was added to the filtrate to give a
pH of about 3, and the precipitated crystals were collected by
filtration. The obtained crystals were dried under reduced pressure
to give 2.1 g of brownish powdery
3-benzyloxy-4-difluoromethoxybenzoic acid.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.78-7.72 (2H, m), 7.73-7.32 (5H,
m), 7.33-7.24 (1H, m), 6.67 (1H, t, J=74.1 Hz), 5.20 (2H, s)
Reference Example 43
A 2 g quantity of 3-benzyloxy-4-difluoromethoxybenzoic acid
obtained in Reference Example 42 was suspended in 40 ml of
dichloromethane, and one drop of dimethylformamide was added. A 0.7
ml quantity of oxalyl chloride was added dropwise with ice-cooling
and stirring. After 2 hours, the reaction mixture was concentrated
under reduced pressure. The residue was dissolved in 5 ml of
acetone and the resulting solution was added dropwise to 28%
aqueous ammonia with ice-cooling and stirring. The obtained mixture
was stirred for 1 hour and the precipitated crystals were collected
by filtration and dried under reduced pressure to give 1.9 g of
white powdery 3-benzyloxy-4-difluoromethoxybenzamide.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.62 (1H, d, J=1.8 Hz), 7.45-7.20
(7H, m), 6.63 (1H, t, J=74.4 Hz), 5.19 (2H, s), 4.73 (2H, br s)
Reference Example 44
A 1.8 g quantity of 3-benzyloxy-4-difluoromethoxybenzamide obtained
in Reference Example 43 was suspended in 50 ml of isopropanol, and
1.17 g of 1,3-dichloro-2-propanone was added. The mixture was
heated and refluxed overnight. The reaction mixture was
concentrated, and the resulting residue was purified by silica gel
column chromatography (dichloromethane). The obtained crude
crystals were recrystallized from isopropanol to give 0.7 g of
white powdery
2-(3-benzyloxy-4-difluoromethoxyphenyl)-4-chloromethyloxazole.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.44 (1H, d, J=1.8 Hz), 7.70 (1H,
s), 7.48-7.32 (5H, m), 7.28-7.24 (1H, m), 6.63 (1H, t, J=74.7 Hz),
5.21 (2H, s), 4.57 (2H, s)
Reference Example 45
A 0.37 g quantity of
2-(3-benzyloxy-4-difluoromethoxyphenyl)-4-chloromethyloxazole
obtained in Reference Example 44 was dissolved in 20 ml of ethanol,
and 0.23 g of sodium iodide and 0.27 g of potassium phthalimide
were added. The mixture was heated and refluxed for 4 hours. After
the reaction mixture was concentrated, water was added to the
residue and extraction with ethyl acetate was performed. The
organic layer was washed with water twice and concentrated by
removing the solvent and the residue was purified by silica gel
column chromatography (dichloromethane:methanol=20:1) to give 0.3 g
of white powdery
2-[2-(3-benzyloxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]isoindolin-1,-
3-dione.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.90-7.84 (2H, m), 7.76-7.71 (4H,
m), 7.59 (1H, dd, J=8.4, 2.1 Hz), 7.47-7.30 (5H, m), 7.22 (1H, d,
J=2.4 Hz), 6.60 (1H, t, J=74.7 Hz), 5.20 (2H, s), 4.87 (2H, s)
Reference Example 46
A 0.3 g quantity of
2-[2-(3-benzyloxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]isoindolin-1,-
3-dione obtained in Reference Example 45 was suspended in 10 ml of
ethanol, and 0.1 ml of hydrazine monohydrate was added. The mixture
was heated and refluxed for 2 hours. After cooling the reaction
mixture, the precipitated insolubles were removed by filtration.
The filtrate was concentrated under reduced pressure to give 0.13 g
of colorless oily
[2-(3-benzyloxy-4-difluoromethoxyphenyl)oxazol-4-yl]methylamine.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.74 (1H, d, J=1.8 Hz), 7.61 (1H,
dd, J=7.8, 1.8 Hz), 7.47 (1H, d, J=1.8 Hz), 7.45-7.31 (5H, m),
7.26-7.20 (1H, m), 6.62 (1H, t, J=74.7 Hz), 5.21 (2H, s), 3.85 (2H,
br s).
Reference Example 47
A 5.25 g quantity of sodium hydride was suspended in 150 ml of
tetrahydrofuran, and a solution of 14.4 g of dimethyl malonate in
75 ml of tetrahydrofuran was added dropwise with ice-cooling over
15 minutes. After stirring for 30 minutes, a solution of 25 g of
the 2-(3-benzyloxy-4-methoxyphenyl)-4-chloromethyloxazole obtained
in Reference Example 5 in 150 ml of dimethylformamide was added
dropwise over 15 minutes. After the dropwise addition, the mixture
was stirred at 50 to 60.degree. C. for 4 hours, and an aqueous
saturated ammonium chloride solution was added with ice-cooling.
After stirring the mixture for 30 minutes, water was added and
extraction with ethyl acetate was performed. The extract was dried
over anhydrous magnesium sulfate, and the solvent was distilled
off. The residue was recrystallized from a mixture of ethyl acetate
and diisopropyl ether to give 26.5 g of white powdery dimethyl
2-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]malonate.
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 7.89 (1H, s), 7.59-7.31 (7H,
m), 7.15 (1H, d, J=7.8 Hz), 5.16 (2H, s), 3.90-3.84 (4H, m), 3.71
(6H, s), 3.04 (2H, d, J=7.8 Hz)
Reference Example 48
A 26.52 g quantity of the dimethyl
2-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]malonate
obtained in Reference Example 47 was suspended in 53 ml of dimethyl
sulfoxide, and 2.62 g of lithium chloride and 1.12 ml of purified
water were added. The mixture was stirred at 130.degree. C. for 4
hours. After the reaction mixture was allowed to cool, water was
added and extraction with ethyl acetate was performed. The extract
was dried over anhydrous magnesium sulfate, and the solvent was
distilled off. The residue was purified by silica gel column
chromatography (n-hexane:ethyl acetate=3:1) to give 16 g of white
powdery methyl
3-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-yl]propionate.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.62-7.59 (2H, m), 7.47 (2H, d,
J=6.9 Hz), 7.40-7.31 (4H, m), 6.93 (1H, d, J=8.4 Hz), 5.20 (2H, s),
3.92 (3H, s), 3.69 (3H, s), 2.91 (2H, t, J=7.2 Hz), 2.72 (2H, t,
J=7.2 Hz)
Reference Example 49
A 0.48 g quantity of sodium hydride was suspended in 15 ml of
tetrahydrofuran, and a solution of 1.31 g of dimethyl malonate in
7.5 ml of tetrahydrofuran was added dropwise over 15 minutes. After
the mixture was stirred for 30 minutes, a solution of 3.0 g of
4-chloromethyl-2-[3-cyclopropylmethoxy-4-(2,2,2-trifluoroethoxy)phenyl]ox-
azole obtained in Reference Example 32 dissolved in 15 ml of
dimethylformamide was added over 15 minutes. After the dropwise
addition, the mixture was heated at 50 to 60.degree. C. with
stirring for 4 hours. An aqueous saturated ammonium chloride
solution was added to the reaction mixture with ice-cooling and
stirred was continued for 30 minutes. Water was added and
extraction with ethyl acetate was performed. The extract was dried
over anhydrous magnesium sulfate, and the solvent was distilled
off. A 8.0 ml quantity of dimethylsulfoxide, 0.35 g of lithium
chloride, and 0.15 ml of purified water were added to the residue,
and the mixture was heated with stirring at 130.degree. C. for 4
hours. After the reaction mixture was allowed to cool, water was
added and extraction with ethyl acetate was performed. The extract
was dried over anhydrous magnesium sulfate and the solvent was
distilled off. The residue was purified by silica gel column
chromatography (n-hexane:ethyl acetate=4:1) to give 1.63 g of
colorless oily methyl
3-{2-[3-cyclopropylmethoxy-4-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-yl}pr-
opionate.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.56-7.53 (2H, m), 7.43 (1H, s),
7.04 (1H, d, J=8.4 Hz), 4.47 (2H, q, J=8.4 Hz), 3.94 (2H, d, J=6.6
Hz), 3.69 (3H, s), 2.91 (2H, t, J=7.2 Hz), 2.72 (2H, t, J=7.2 Hz),
0.88 (1H, t, J=6.6 Hz), 0.69-0.65 (2H, m), 0.40-0.35 (2H, m)
Reference Example 50
A 0.5 g quantity of 2-cyclopropylethanol and 3.1 ml of
triethylamine were dissolved in 10 ml of ethyl acetate, and 0.75 ml
of methanesulfonyl chloride was added with ice-cooling and
stirring. After stirring for 30 minutes, water was added to the
reaction mixture and extraction was performed. The organic layer
was washed with water twice and concentrated by removing the
solvent under reduced pressure to give 1 g of pale yellow oily
2-cyclopropylethyl methanesulfonate.
.sup.1H-NMR (CDCl.sub.3) .delta.: 4.29 (2H, t, J=6.6 Hz), 3.03 (3H,
s), 1.66 (2H, q, J=6.6 Hz), 0.84-0.70 (1H, m), 0.54-0.47 (2H, m),
0.20-0.10 (2H, m)
Reference Example 51
Using 2 g of 2-cyclopentylethanol and following the procedure of
Reference Example 50, 3.4 g of pale yellow oily 2-cyclopentylethyl
methanesulfonate was obtained.
.sup.1H-NMR (CDCl.sub.3) .delta.: 4.24 (2H, t, J=6.6 Hz), 3.03 (3H,
s), 1.95-1.73 (5H, m), 1.70-1.48 (4H, m), 1.29-1.06 (2H, m)
Reference Example 52
Using 0.5 g of cyclopentylmethanol and following the procedure of
Reference Example 50, 0.7 g of pale yellow oily cyclopentylmethyl
methanesulfonate was obtained.
.sup.1H-NMR (CDCl.sub.3) .delta.: 4.11 (2H, d, J=6.9 Hz), 3.04 (3H,
s), 2.38-2.23 (1H, m), 1.86-1.76 (2H, m), 1.74-1.53 (4H, m),
1.36-1.24 (2H, m)
Reference Example 53
A 25 g quantity of 1-(2-hydroxyphenyl)ethanone and 76 g of
potassium carbonate were suspended in 500 ml of acetonitrile, and
31 ml of allyl bromide was added. The mixture was stirred at room
temperature for 48 hours. The reaction mixture was filtered to
remove insolubles, and the filtrate was concentrated under reduced
pressure. The obtained residue was purified by silica gel column
chromatography (n-hexane:ethyl acetate=4:1) to give 34 g of pale
yellow oily 1-(2-allyloxyphenyl)ethanone.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.73 (1H, dd, J=7.8, 1.8 Hz),
7.46-7.40 (1H, m), 7.02-6.93 (2H, m), 6.15-6.02 (1H, m), 5.47-5.30
(2H, m), 4.66-4.61 (2H, m), 2.64 (3H, s)
Reference Example 54
A 40 g quantity of 3,4-diethoxybenzamide and 80 g of methyl
5-bromo-4-oxopentanoate (containing about 35% of methyl
3-bromo-4-oxopentanoate) were added to 400 ml of dimethylformamide,
and the mixture was stirred at 130.degree. C. for 16 hours. The
reaction mixture was concentrated under reduced pressure and
diluted with ethyl acetate. Ethyl acetate (500 ml) and saturated
sodium bicarbonate solution (500 ml) were gradually added with
stirring, and stirring was continued. The organic layer was dried
over anhydrous magnesium sulfate and then concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (ethyl acetate:n-hexane=1:8 to 1:4) to give 18 g of
white powdery methyl
3-[2-(3,4-diethoxyphenyl)oxazol-4-yl]propionate.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.65-7.55 (2H, m), 7.51 (1H, s),
6.93 (1H, d, J=8.1 Hz), 4.19 (2H, q, J=6.9 Hz), 4.15 (2H, q, J=6.9
Hz), 3.80 (3H, s), 3.00-2.90 (2H, m), 2.70-2.60 (2H, m), 1.50 (3H,
t, J=6.9 Hz), 1.49 (3H, t, J=6.9 Hz)
Reference Example 55
A 37.9 g quantity of 3,4-dibenzyloxybenzamide and 28.8 g of
1,3-dichloro-2-propanone were suspended in 500 ml of propanol, and
the suspension was heated and refluxed for 3 days. After cooling,
the reaction mixture was concentrated to half its original volume
under reduced pressure and 300 ml of diisopropyl ether was added.
The precipitated crystals were collected by filtration and
recrystallized from acetone-methanol-diisopropyl ether. The
obtained crystals were dried under reduced pressure to give 20.1 g
of colorless powdery
2-(3,4-bis(benzyloxy)phenyl)-4-chloromethyloxazole.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.66 (1H, d, J=2.1 Hz), 7.64 (1H,
s), 7.59 (1H, dd, J=8.4, 2.1 Hz), 7.50-7.28 (10H, m), 6.99 (1H, d,
J=8.4 Hz), 5.22 (2H, s), 5.21 (2H, s), 4.55 (2H, s)
Reference Example 56
Using 10 g of 2-(3,4-bis(benzyloxy)phenyl)-4-chloromethyloxazole
obtained in Reference Example 55 and following the procedure of
Reference Example 47, 12.3 g of colorless oily dimethyl
2-[2-(3,4-bis(benzyloxy)phenyl)oxazol-4-ylmethyl]malonate was
obtained.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.61 (1H, d, J=2.1 Hz), 7.58-7.27
(12H, m), 6.97 (1H, d, J=8.4 Hz), 5.23-5.20 (4H, m), 3.89 (1H, t,
J=7.5 Hz), 3.75 (3H, s), 3.73 (3H, s), 3.18 (2H, d, J=7.5 Hz)
Reference Example 57
Using 12.3 g of dimethyl
2-[2-(3,4-bis(benzyloxy)phenyl)oxazol-4-ylmethyl]malonate obtained
in Reference Example 56 and following the procedure of Reference
Example 48, 4 g of pale red powdery methyl
3-[2-(3,4-bis(benzyloxy)phenyl)oxazol-4-yl]propionate was
obtained.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.63 (1H, d, J=2.1 Hz), 7.57-7.27
(12H, m), 6.97 (1H, d, J=8.4 Hz), 5.21 (2H, d, J=7.2 Hz), 3.69 (3H,
s), 2.90 (2H, t, J=7.2 Hz), 2.72 (2H, d, J=7.2 Hz)
Reference Example 58
Using 29.4 g of 3-ethoxy-4-methoxybenzamide and 57 g of
1,3-dichloro-2-propanone and following the procedure of Reference
Example 55, 19.9 g of white powdery
4-chloromethyl-2-(3-ethoxy-4-methoxyphenyl)oxazole was
obtained.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.65 (1H, s), 7.61 (1H, dd,
J=8.1, 2.1 Hz), 7.55 (1H, d, J=2.1 Hz), 6.92 (1H, d, J=8.1 Hz),
4.56 (2H, s), 4.18 (2H, q, J=6.9 Hz), 3.93 (3H, s), 1.50 (3H, t,
J=6.9 Hz)
Reference Example 59
A 25 g quantity of ethyl 3,4-dihydroxybenzoate was dissolved in 250
ml of dimethylformamide, and 5.5 g of sodium hydride was added with
ice-cooling and stirring. The mixture was stirred, and a solution
of 16.3 ml of benzylbromide in 10 ml of dimethylformamide was added
dropwise. After the dropwise addition, the mixture was stirred at
room temperature overnight. Water was added to the reaction mixture
and extraction with ethyl acetate was performed. The organic layer
was washed with water twice and concentrated by removing the
solvent under reduced pressure. The obtained residue was purified
by silica gel column chromatography (n-hexane:ethyl acetate=2:1) to
give 15 g of crude crystals. The crude crystals were recrystallized
from a mixture of 30 ml of n-hexane and 15 ml of ethyl acetate to
give 8.6 g of colorless plate crystalline ethyl
4-benzyloxy-3-hydroxybenzonate.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.67-7.47 (2H, m), 7.41-7.30 (5H,
m), 6.94 (1H, d, J=8.7 Hz), 5.67 (1H, s), 5.16 (2H, s), 4.34 (2H,
q, J=7.2 Hz), 1.37 (3H, t, J=7.2 Hz)
Reference Example 60
Using ethyl 4-benzyloxy-3-hydroxybenzonate obtained in Reference
Example 59 and following the procedure of Reference Example 2,
ethyl 4-benzyloxy-3-ethoxybenzoate was obtained.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.61-7.55 (2H, m), 7.45-7.27 (5H,
m), 6.90 (1H, d, J=8.1 Hz), 5.21 (2H, s), 4.34 (2H, q, J=6.9 Hz),
4.17 (2H, q, J=6.9 Hz), 1.48 (3H, t, J=6.9 Hz), 1.37 (3H, t, J=6.9
Hz)
Reference Example 61
Using ethyl 4-benzyloxy-3-ethoxybenzoate obtained in Reference
Example 60 and following the procedure of Reference Example
3,4-benzyloxy-3-ethoxybenzoic acid was obtained.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.68 (1H, dd, J=8.4, 1.2 Hz),
7.61 (1H, d, J=1.2 Hz), 7.45-7.28 (5H, m), 6.92 (1H, d, J=8.4 Hz),
5.23 (2H, s), 4.17 (2H, q, J=6.9 Hz), 1.48 (3H, t, J=6.9 Hz)
Reference Example 62
Using 4-benzyloxy-3-ethoxybenzoic acid obtained in Reference
Example 61 and following the procedure of Reference Example 4,
colorless needle crystalline 4-benzyloxy-3-ethoxybenzamide was
obtained.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.47-7.21 (7H, m), 6.88 (1H, d,
J=8.1 Hz), 5.21 (2H, s), 4.18 (2H, q, J=7.2 Hz), 1.48 (3H, t, J=7.2
Hz)
Reference Example 63
Using 4-benzyloxy-3-ethoxybenzamide obtained in Reference Example
62 and following the procedure of Reference Example 5, colorless
powdery 4-chloromethyl-2-(4-benzyloxy-3-ethoxyphenyl)oxazole was
obtained.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.64 (1H, s), 7.57-7.30 (7H, m),
6.94 (1H, d, J=8.4 Hz), 5.20 (2H, s), 4.56 (2H, s), 4.20 (2H, q,
J=7.2 Hz), 1.49 (3H, t, J=7.2 Hz)
Reference Example 64
A 6.81 g quantity of sodium iodide and 5.09 g of sodium bicarbonate
were added to a suspension of 10 g of
2-(3-benzyloxy-4-methoxyphenyl)-4-chloromethyloxazole obtained in
Reference Example 5 in 60 ml of dimethylsulfoxide. The mixture was
heated at 120.degree. C. with stirring for 30 minutes. After the
reaction mixture was allowed to cool, saturated brine was added and
extraction with ethyl acetate was performed. The organic layer was
washed with saturated brine and dried over anhydrous magnesium
sulfate, and the solvent was then distilled off under reduced
pressure. The obtained residue was purified by silica gel column
chromatography (n-hexane:ethyl acetate=3:1) to give 2.98 g of
yellow oily
2-(3-benzyloxy-4-methoxyphenyl)oxazole-4-carbaldehyde.
.sup.1H-NMR (CDCl.sub.3) .delta.: 9.98 (1H, s), 8.26 (1H, s), 7.71
(1H, dd, J=8.1, 2.1 Hz), 7.69 (1H, br s), 7.48 (2H, br d, J=8.4
Hz), 7.42-7.31 (3H, m), 6.98 (1H, d, J=8.1 Hz), 5.21 (2H, s), 3.95
(3H, s)
Reference Example 65
Using
4-chloromethyl-2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazole
obtained in Reference Example 23 and following the procedure of
Reference Example 64, colorless powdery
2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazole-4-carbaldehyde
was obtained.
.sup.1H-NMR (CDCl.sub.3) .delta.: 9.99 (1H, s), 8.28 (1H, s), 7.82
(1H, dd, J=8.4, 2.1 Hz), 7.71 (1H, d, J=2.1 Hz), 7.01 (1H, d, J=8.4
Hz), 4.46 (2H, q, J=8.4 Hz), 3.95 (3H, s)
Reference Example 66
Using 4-chloromethyl-2-(3,4-diethoxyphenyl)oxazole obtained in
Reference Example 35 and following the procedure of Reference
Example 64, pale yellow powdery
2-(3,4-diethoxyphenyl)oxazole-4-carbaldehyde was obtained.
.sup.1H-NMR (CDCl.sub.3) .delta.: 9.99 (1H, s), 8.26 (1H, s), 7.65
(1H, dd, J=8.4, 2.1 Hz), 7.62 (1H, d, J=2.1 Hz), 6.94 (1H, d, J=8.4
Hz), 4.19 (2H, q, J=7.2 Hz), 4.17 (2H, q, J=7.2 Hz), 1.50 (6H, t,
J=7.2 Hz)
Reference Example 67
Using 12.7 g of 3-isopropoxy-4-methoxybenzoic acid and following
the procedure of Reference Example 4, white powdery
3-isopropoxy-4-methoxybenzamide was obtained.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.46 (1H, d, J=2.1 Hz), 7.34 (1H,
dd, J=8.4, 2.1 Hz), 6.87 (1H, d, J=8.4 Hz), 5.93 (1H, br s), 4.62
(1H, m), 3.90 (3H, s), 1.38 (6H, d, J=6.0 Hz).
Reference Example 68
Using 11.4 g of 3-isopropoxy-4-methoxybenzamide obtained in
Reference Example 67 and 25 g of 1,3-dichloro-2-propanone and
following the procedure of Reference Example 5, 12.2 g of white
powdery 4-chloromethyl-2-(3-isopropoxy-4-methoxyphenyl)oxazole was
obtained.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.65 (1H, s), 7.61 (1H, dd,
J=8.4, 2.1 Hz), 7.57 (1H, d, J=2.1 Hz), 6.93 (1H, d, J=8.4 Hz),
4.64 (1H, m), 4.53 (2H, s), 3.90 (3H, s), 1.40 (6H, d, J=6.0
Hz)
Reference Example 69
Using 4-chloromethyl-2-(3-isopropoxy-4-methoxyphenyl) oxazole
obtained in Reference Example 68 and following the procedure of
Reference Example 64, pale yellow powdery
2-(3-isopropoxy-4-methoxyphenyl)oxazole-4-carbaldehyde was
obtained.
.sup.1H-NMR (CDCl.sub.3) .delta.: 9.99 (1H, s), 8.27 (1H, s), 7.68
(1H, dd, J=8.1, 2.1 Hz), 7.64 (1H, d, J=2.1 Hz), 6.95 (1H, d, J=8.1
Hz), 4.67 (1H, sept., J=6.3 Hz), 3.92 (3H, s), 1.41 (6H, d, J=6.3
Hz)
Reference Example 70
A 10 g quantity of 1-(2-hydroxyphenyl)ethanone was dissolved in 100
ml of dimethylformamide, and 11.2 ml of chloromethyl methyl ether
and 25.4 g of potassium carbonate were added. The mixture was
stirred at 50.degree. C. for 6 hours and then at room temperature
for 4 days. After insolubles were removed from the reaction mixture
by filtration, ice water was added to the filtrate and extraction
with ethyl acetate was performed. The organic layer was washed with
water and dried over anhydrous magnesium sulfate. The organic layer
was concentrated under reduced pressure, and the residue was
purified by silica gel column chromatography (n-hexane:ethyl
acetate=5:1) to give 6.26 g of colorless oily
1-(2-methoxymethoxyphenyl)ethanone.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.71 (1H, dd, J=7.8, 1.8 Hz),
7.43 (1H, td, J=7.8, 1.8 Hz), 7.18 (1H, d, J=7.8 Hz), 7.05 (1H, t,
J=7.8 Hz), 5.28 (2H, s), 3.52 (3H, s), 2.64 (3H, s)
Reference Example 71
A 3 g quantity of methyl
3-[2-(3,4-diethoxyphenyl)oxazol-4-yl]propionate obtained in
Reference Example 54 was suspended in 5 ml of methanol, and 5 ml of
a 20% aqueous sodium hydroxide solution was added. The mixture was
heated and refluxed for 4 hours. After cooling the reaction mixture
to room temperature, extraction with dichloromethane was performed.
The dichloromethane layer was washed with water and dried over
anhydrous magnesium sulfate. The solvent was distilled off and the
obtained crystals were dried to give 2.8 g of white powdery
3-[2-(3,4-dimethoxyphenyl)oxazol-4-yl]propionic acid.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.65-7.55 (3H, m), 7.51 (1H, d,
J=2.1 Hz), 6.91 (1H, d, J=8.4 Hz), 4.17 (2H, q, J=6.9 Hz), 4.15
(2H, q, J=6.9 Hz), 3.00-2.90 (2H, m), 2.90-2.80 (2H, m), 1.48 (3H,
t, J=6.9 Hz), 1.48 (3H, t, J=6.9 Hz)
Reference Example 72
Using 10 g of 4-benzyloxy-3-methoxybenzamide and following the
procedure of Reference Example 54, 2 g of white powdery methyl
3-[2-(4-benzyloxy-3-methoxyphenyl)oxazol-4-yl]propionate was
obtained.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.54-7.28 (8H, m) 6.93 (1H, d,
J=8.1 Hz), 5.20 (2H, s), 3.97 (3H, s), 3.68 (3H, s), 2.91 (2H, t,
J=7.5 Hz), 2.64 (2H, t, J=7.5 Hz)
Reference Example 73
Using 2 g of methyl
3-[2-(4-benzyloxy-3-methoxyphenyl)oxazol-4-yl]propionate obtained
in Reference Example 72 and following the procedure of Reference
Example 71, 1.03 g of white powdery
3-[2-(4-benzyloxy-3-methoxyphenyl)oxazol-4-yl]propionic acid was
obtained.
.sup.1H-NMR (CDCl.sub.3) .delta.: 12.20 (1H, s), 7.86 (1H, s),
7.51-7.31 (7H, m) 7.17 (1H, d, J=8.4 Hz), 5.15 (2H, s), 3.85 (3H,
s), 2.75 (2H, t, J=7.5 Hz), 2.59 (2H, t, J=7.5 Hz)
Reference Example 74
A 0.4 g quantity of 4-chloromethyl-2-(3,4-diethoxy phenyl)oxazole
obtained in Reference Example 35 was dissolved in 15 ml of
methylamine (40% methanol solution), and was heated and refluxed
for 1 hour. The reaction mixture was concentrated and the obtained
residue was dried under reduced pressure to give 0.23 g of yellow
oily [2-(3,4-dimethoxyphenyl)oxazol-4-ylmethyl]methylamine.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.00 (1H, s), 7.58-7.50 (2H, m),
6.90 (1H, d, J=8.4 Hz), 4.21-4.10 (6H, m), 2.76 (3H, s), 1.51-1.45
(6H, m)
Reference Example 75
Using ethyl 2-chloroacetoacetate and 16 g of 3,4-diethoxybenzamide
and following the procedure of Reference Example 5, 3.8 g of ethyl
[2-(3,4-dimethoxyphenyl)oxazol-4-yl]acetate was obtained.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.64 (1H, s), 7.60-7.50 (2H, m),
6.91 (1H, d, J=8.1 Hz), 4.25-4.10 (6H, m), 3.58 (2H, s), 1.50-1.40
(6H, m), 1.29 (3H, t, J=6.9 Hz)
Reference Example 76
A 0.35 g quantity of lithium aluminum hydride was added to 30 ml of
tetrahydrofuran with ice-cooling and stirring, and ethyl
[2-(3,4-dimethoxyphenyl)oxazol-4-yl]acetate obtained in Reference
Example 75 was slowly added with stirring. After stirring at room
temperature for 3 hours, the mixture was stirred with ice-cooling
for 3 hours, and 0.35 ml of water, 0.35 ml of a 15% aqueous sodium
hydroxide solution, and 1.05 ml of water were added in that order.
The reaction mixture was dried over anhydrous magnesium sulfate,
and insolubles were then removed by filtration. The filtrate was
concentrated under reduced pressure to give 2.5 g of colorless
crystalline 2-[2-(3,4-dimethoxyphenyl)oxazol-4-yl]ethanol.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.56 (1H, d, J=8.4, 2.1 Hz), 7.52
(1H, d, J=2.1 Hz), 7.46 (1H, s), 6.91 (1H, d, J=8.4 Hz), 4.17 (2H,
q, J=7.2 Hz), 4.15 (2H, q, J=7.2 Hz), 3.94 (2H, q, J=5.4 Hz), 2.94
(1H, t, J=5.4 Hz), 2.81 (2H, t, J=5.4 Hz), 1.48 (3H, t, J=7.2 Hz),
1.48 (3H, t, J=7.2 Hz)
Reference Example 77
A 2.0 g quantity of 2-[2-(3,4-dimethoxyphenyl)oxazol-4-yl]ethanol
obtained in Reference Example 76 and 2.3 g of triphenylphosphine
were added to 20 ml of dichloromethane, and 2.9 g of carbon
tetrabromide was slowly added with ice-cooling and stirring. After
the temperature of the mixture had reached room temperature,
stirring was continued for 1.5 hours. The reaction mixture was
concentrated, and the residue was purified by silica gel column
chromatography (n-hexane:ethyl acetate=8:1) to give 1.9 g of
colorless crystalline
4-(2-bromoethyl)-2-(3,4-diethoxyphenyl)oxazole.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.60-7.50 (3H, m), 6.91 (1H, d,
J=8.4 Hz), 4.18 (2H, q, J=7.2 Hz), 4.14 (2H, q, J=7.2 Hz), 3.67
(2H, t, J=6.9 Hz), 3.14 (2H, t, J=6.9 Hz), 1.48 (3H, t, J=7.2 Hz),
1.48 (3H, t, J=7.2 Hz)
Reference Example 78
Using 1.5 g of 4-(2-bromoethyl)-2-(3,4-diethoxyphenyl)oxazole
obtained in Reference Example 77 and following the procedures of
Reference Examples 6 and 7, 0.8 g of yellow oily
2-[2-(3,4-diethoxyphenyl)oxazol-4-yl]ethylamine was obtained.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.60-7.50 (3H, m), 6.91 (1H, d,
J=8.4 Hz), 4.17 (2H, q, J=7.2 Hz), 4.15 (2H, q, J=7.2 Hz),
3.90-3.80 (2H, m), 3.00-2.90 (2H, m), 1.85 (2H, brs), 1.48 (3H, t,
J=7.2 Hz), 1.48 (3H, t, J=7.2 Hz)
Reference Example 79
Using 10.4 g of 3,4-diethoxybenzamide and 19.5 g of ethyl
3-bromo-2-oxopropionate and following the procedure of Reference
Example 5, 12.9 g of white powdery ethyl
2-(3,4-diethoxyphenyl)oxazole-4-carboxylate was obtained.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.21 (1H, d, J=0.9 Hz), 7.64 (1H,
dd, J=8.1, 0.9 Hz), 7.63 (1H, s), 6.92 (1H, d, J=8.1 Hz), 4.42 (2H,
q, J=7.2 Hz), 4.17 (2H, q, J=6.9 Hz), 4.15 (2H, q, J=6.9 Hz), 1.48
(3H, t, J=6.9 Hz), 1.41 (3H, t, J=7.2 Hz)
Reference Example 80
Using 10 g of the ethyl 2-(3,4-diethoxyphenyl)oxazole-4-carboxylate
obtained in Reference Example 79 and following the procedure of
Reference Example 71, 8.6 g of white powdery
2-(3,4-diethoxyphenyl)oxazole-4-carboxylic acid was obtained.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.24 (1H, s), 7.60-7.50 (3H, m),
6.02 (1H, brs), 4.13 (4H, q, J=6.9 Hz), 1.46 (3H, t, J=6.9 Hz),
1.39 (3H, t, J=6.9 Hz)
Reference Example 81
Using 0.4 g of ethyl [2-(3,4-diethoxyphenyl)oxazol-4-yl]acetate
obtained in Reference Example 75 and following the procedure of
Reference Example 71, 0.35 g of white powdery
[2-(3,4-diethoxyphenyl)oxazol-4-yl]acetic acid was obtained.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.65-7.55 (3H, m), 7.51 (1H, d,
J=2.1 Hz), 6.91 (1H, d, J=8.4 Hz), 4.17 (2H, q, J=6.9 Hz), 4.15
(2H, q, J=6.9 Hz), 3.73 (2H, s), 1.49 (6H, t, J=6.9 Hz)
Reference Example 82
Using 3 g of
4-chloromethyl-2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazole
obtained in Reference Example 23 and following the procedure of
Reference Example 47, 1.91 g of colorless oily dimethyl
2-{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-ylmethyl}malonat-
e was obtained.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.70 (1H, dd, J=8.4, 2.1 Hz),
7.60 (1H, d, J=2.1 Hz), 7.42 (1H, s), 6.96 (1H, d, J=8.4 Hz), 4.44
(2H, q, J=6.9 Hz), 3.93 (3H, s), 3.89 (1H, t, J=7.5 Hz), 3.18 (2H,
d, J=7.5 Hz)
Reference Example 83
Using 1.9 g of dimethyl
2-{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-ylmethyl}malonat-
e obtained in Reference Example 82 and following the procedure of
Reference Example 48, 1.44 g of colorless oily methyl
3-{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-yl}propionate
was obtained.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.70 (1H, dd, J=8.4, 2.1 Hz),
7.60 (1H, d, J=2.1 Hz), 7.42 (1H, s), 6.96 (1H, d, J=8.4 Hz), 4.45
(2H, q, J=6.9 Hz), 3.92 (3H, s), 3.75 (3H, s), 2.91 (2H, t, J=7.5
Hz), 2.72 (2H, t, J=7.5 Hz)
Example 1
A 3.5 g quantity of the [2-(3-benzyloxy-4-methoxy
phenyl)oxazol-4-yl]methylamine obtained in Reference Example 7 was
suspended in 70 ml of acetone. To the obtained suspension were
added 2.3 g of 1-hydroxybenzotriazole, 3.3 g of
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 3.8
g of 2-ethoxybenzoic acid, and the mixture was heated and refluxed
for one hour. The reaction mixture was cooled, and acetone was
distilled off under reduced pressure. Water was added to the
residue, and extraction was then performed with ethyl acetate. The
organic layer was washed with water twice, and concentrated under
reduced pressure. The obtained residue was purified by silica gel
column chromatography (dichloromethane:methanol=20:1) to give 4.6 g
of white powdery
N-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.55 (1H, br s) 8.23 (1H, dd,
J=7.8, 1.8 Hz), 7.65-7.61 (3H, m), 7.49-7.29 (6H, m), 7.09 (1H, t,
J=7.5 Hz), 7.04-6.92 (2H, m), 5.20 (2H, s), 4.61 (2H, d, J=5.4 Hz),
4.16 (2H, q, J=6.9 Hz), 3.93 (3H, s), 1.26 (3H, t, J=6.9 Hz)
Example 2
A 4.65 g quantity of the
N-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide
obtained in Example 1 was dissolved in 90 ml of ethanol, and 0.45 g
of 10% palladium carbon powder was added thereto. The mixture was
stirred in a hydrogen atmosphere at room temperature for one hour.
The catalyst was removed by filtration, and the filtrate was then
concentrated under reduced pressure to give 3.7 g of white
crystalline
N-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.58 (1H, br s) 8.23 (1H, dd,
J=7.8, 1.8 Hz), 7.62-7.55 (3H, m), 7.41 (1H, td, J=7.5 Hz, 1.8 Hz),
7.06 (1H, t, J=7.2 Hz), 6.95-6.88 (2H, m), 5.74 (1H, s), 4.62 (2H,
d, J=5.1 Hz), 4.17 (2H, q, J=6.9 Hz), 3.95 (3H, s), 1.47 (3H, t,
J=6.9 Hz)
Example 3
A 0.2 g quantity of the N-[2-(3-hydroxy-4-methoxy
phenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide obtained in Example 2
and 0.3 ml of 1,8-diazabicyclo[5,4,0]undec-7-ene were dissolved in
4 ml of ethanol, and 0.14 g of (bromomethyl)cyclopropane was added
thereto. The mixture was heated and refluxed overnight. The
reaction mixture was allowed to cool, water was then added thereto,
and extraction was performed with ethyl acetate. After washing with
water twice, the organic layer was concentrated under reduced
pressure. The obtained residue was purified by silica gel column
chromatography (n-hexane:ethyl acetate=3:1) to give 0.18 g of white
powdery
N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-ethoxyben-
zamide.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.55 (1H, br s) 8.24 (1H, dd,
J=7.8, 2.1 Hz), 7.62-7.59 (2H, m), 7.53 (1H, d, J=2.1 Hz),
7.45-7.39 (1H, m), 7.07 (1H, td, J=8.1 Hz, 1.2 Hz), 6.95-6.91 (2H,
m), 4.62 (2H, d, J=5.4 Hz), 4.18 (2H, q, J=6.9 Hz), 3.94-3.92 (5H,
m), 1.49 (3H, t, J=6.9 Hz), 1.42-1.34 (1H, m), 0.71-0.64 (2H, m),
0.41-0.35 (2H, m)
Example 4
A 0.3 g quantity of the N-[2-(3-hydroxy-4-methoxy
phenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide obtained in Example 2
and 0.22 g of potassium carbonate were dissolved in 10 ml of
dimethylformamide, and 0.34 g of 1,1,1-trifluoro-2-iodoethane was
added thereto. The mixture was stirred with heating at 50.degree.
C. overnight. The reaction mixture was allowed to cool, water was
then added thereto, and extraction was performed with ethyl
acetate. After washing with water twice, the organic layer was
concentrated under reduced pressure. The obtained residue was
purified by silica gel column chromatography (n-hexane:ethyl
acetate=3:1) to give 0.14 g of white powdery
N-{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-ylmethyl}-2-etho-
xybenzamide.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.56 (1H, br s) 8.24 (1H, dd,
J=7.8, 2.1 Hz), 7.73 (1H, dd, J=8.4, 2.1 Hz), 7.65-7.63 (2H, m),
7.45-7.39 (1H, m), 7.09-7.01 (1H, m), 6.99-6.90 (2H, m), 4.62 (2H,
d, J=5.4 Hz), 4.55 (2H, q, J=8.4 Hz), 4.32 (2H, q, J=6.9 Hz), 3.93
(3H, s), 1.49 (3H, t, J=6.9 Hz)
Using 0.2 g of the
N-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide
obtained in Example 2, compounds of Examples 5 to 14 were obtained
in the same manner as in Example 3.
Example 5
N-[2-(3-butoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-ethoxy
benzamide
Yield 0.2 g
White Powder
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.56 (1H, br s) 8.24 (1H, dd,
J=7.8, 2.1 Hz), 7.62-7.54 (3H, m), 7.45-7.39 (1H, m), 7.07 (1H, t,
J=8.1 Hz), 6.96-6.90 (2H, m), 4.62 (2H, d, J=5.4 Hz), 4.18 (2H, q,
J=6.9 Hz), 4.10 (2H, t, J=6.9 Hz), 3.92 (3H, s), 1.92-1.82 (2H, m),
1.59-1.47 (5H, m) 1.00 (3H, t, J=7.5 Hz)
Example 6
N-[2-(3-cyclopentyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamid-
e
Yield 0.22 g
Colorless Oily Substance
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.57 (1H, br s) 8.24 (1H, dd,
J=7.8, 2.1 Hz), 7.62-7.54 (3H, m), 7.45-7.39 (1H, m), 7.07 (1H, t,
J=8.1 Hz), 6.96-6.90 (2H, m), 4.91-4.86 (1H, m), 4.62 (2H, d, J=5.4
Hz), 4.17 (2H, q, J=6.9 Hz), 3.90 (3H, s), 2.02-1.60 (8H, m), 1.49
(3H, t, J=6.9 Hz)
Example 7
N-{2-[3-(3-hydroxypropoxy)-4-methoxyphenyl]oxazol-4-ylmethyl}-2-ethoxybenz-
amide
Yield 0.12 g
White Powder
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.56 (1H, br s) 8.24 (1H, d,
J=7.8 Hz), 7.62-7.54 (3H, m), 7.45-7.39 (1H, m), 7.09-7.06 (1H, m),
6.96-6.90 (2H, m), 4.62 (2H, d, J=5.4 Hz), 4.29-4.16 (4H, m),
3.92-3.79 (5H, m), 2.57 (1H, br s), 2.12 (2H, t, J=5.4 Hz), 1.49
(3H, t, J=6.9 Hz)
Example 8
N-[2-(4-methoxy-3-(2-propynyloxy)phenyl)oxazol-4-ylmethyl]-2-ethoxybenzami-
de
Yield 0.19 g
White Powder
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.58 (1H, br s) 8.24 (1H, dd,
J=7.8, 1.8 Hz), 7.70-7.63 (3H, m), 7.45-7.39 (1H, m), 7.07 (1H, td,
J=8.4, 0.9 Hz), 6.98-6.93 (2H, m), 4.84 (2H, d, J=2.4 Hz), 4.63
(2H, dd, J=5.4, 0.9 Hz), 4.19 (2H, q, J=7.2 Hz), 3.94 (3H, s), 2.54
(1H, t, J=2.4 Hz), 1.50 (3H, t, J=7.2 Hz)
Example 9
N-[2-(3-ethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-ethoxy
benzamide
Yield 0.22 g
White Powdery
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.55 (1H, br s) 8.24 (1H, dd,
J=7.8, 1.8 Hz), 7.62-7.54 (3H, m), 7.44-7.39 (1H, m), 7.07 (1H, t,
J=8.1 Hz), 6.96-6.91 (2H, m), 4.62 (2H, d, J=5.4 Hz), 4.23-4.14
(4H, m), 3.93 (3H, s), 1.53-1.46 (6H, m)
Example 10
N-[2-(4-methoxy-3-(2-oxiranylmethoxy)phenyl)oxazol-4-ylmethyl]-2-ethoxyben-
zamide
Yield 27 mg
White Powder
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.54 (1H, br s) 8.24 (1H, dd,
J=7.8, 1.8 Hz), 7.67-7.58 (3H, m), 7.45-7.38 (1H, m), 7.07 (1H, t,
J=7.8 Hz), 6.95 (2H, d, J=8.4 Hz), 4.62 (2H, d, J=5.1 Hz),
4.36-4.07 (4H, m), 3.93 (3H, s), 3.46-3.41 (1H, m), 2.92 (1H, t,
J=4.5 Hz), 2.80-2.76 (1H, m), 1.48 (3H, t, J=7.2 Hz)
Example 11
N-[2-(4-methoxy-3-propoxyphenyl)oxazol-4-ylmethyl]-2-ethoxy
benzamide
Yield 0.19 g
White Powder
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.56 (1H, br s) 8.24 (1H, dd,
J=7.8, 1.8 Hz), 7.63-7.54 (3H, m), 7.45-7.39 (1H, m), 7.07 (1H, td,
J=8.4, 1.2 Hz), 6.96-6.91 (2H, m), 4.63 (2H, dd, J=5.1, 0.9 Hz),
4.18 (2H, q, J=6.9 Hz), 4.06 (2H, t, J=6.9 Hz), 3.92 (3H, s),
1.97-1.85 (2H, m), 1.49 (3H, t, J=6.9 Hz), 1.07 (3H, t, J=7.2
Hz)
Example 12
N-[2-(3-isopropoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-ethoxy
benzamide
Yield 0.17 g
White Powder
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.57 (1H, br s) 8.24 (1H, dd,
J=7.8, 1.8 Hz), 7.62-7.55 (3H, m), 7.45-7.38 (1H, m), 7.07 (1H, t,
J=7.8 Hz), 6.96-6.91 (2H, m), 4.72-4.59 (3H, m), 4.18 (2H, q, J=6.9
Hz), 3.91 (3H, s), 1.49 (3H, t, J=6.9 Hz), 1.41 (6H, d, J=6.3
Hz)
Example 13
N-[2-(3-(3-butenyloxy)-4-methoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamid-
e
Yield 0.21 g
White Powder
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.56 (1H, br s) 8.23 (1H, dd,
J=7.8, 1.8 Hz), 7.63-7.55 (3H, m), 7.45-7.38 (1H, m), 7.07 (1H, t,
J=7.8 Hz), 6.96-6.91 (2H, m), 5.97-5.88 (1H, m), 5.23-5.10 (2H, m),
4.62 (2H, dd, J=5.1, 0.9 Hz), 4.21-4.12 (4H, m), 3.92 (3H, s),
2.68-2.60 (2H, m), 1.49 (3H, t, J=6.9 Hz)
Example 14
N-[2-(3-isobutoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-ethoxy
benzamide
Yield 84 mg
White Powder
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.54 (1H, br s), 8.23 (1H, dd,
J=7.8, 1.8 Hz) 7.62-7.53 (2H, m), 7.44 (1H, d, J=1.8 Hz), 7.41 (2H,
td, J=7.8, 1.8 Hz), 7.06 (1H, t, J=7.8 Hz), 6.95-6.90 (2H, m), 4.62
(2H, d, J=5.4 Hz), 4.18 (2H, q, J=6.9 Hz), 3.91 (3H, s), 3.85 (2H,
d, J=6.9 Hz), 2.20 (1H, qt, J=6.9, 6.6 Hz), 1.49 (3H, t, J=6.9 Hz),
1.06 (6H, d, J=6.6 Hz)
Example 15
Using 0.2 g of the
N-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide
obtained in Example 2,
N-{2-[4-methoxy-3-(3,3,3-trifluoropropoxy)phenyl]oxazol-4-ylmethyl}-2-eth-
oxybenzamide was obtained in the same manner as in Example 4.
Yield 60 mg
White Powder
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.55 (1H, br s) 8.23 (1H, dd,
J=7.8, 1.8 Hz), 7.68-7.63 (2H, m), 7.56 (1H, d, J=2.1 Hz),
7.45-7.39 (1H, m), 7.07 (1H, t, J=7.2 Hz), 6.97-6.93 (2H, m), 4.62
(2H, d, J=5.4 Hz), 4.32 (2H, t, J=6.9 Hz), 4.18 (2H, q, J=6.9 Hz),
3.92 (3H, s), 2.78-2.67 (2H, m), 1.49 (3H, t, J=6.9 Hz)
Example 16
A 1.5 g quantity of the [2-(3-benzyloxy-4-methoxy
phenyl)oxazol-4-yl]methylamine obtained in Reference Example 7 was
suspended in 30 ml of acetone. To the obtained suspension were
added 1.0 g of 1-hydroxybenzotriazole, 1.4 g of
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 0.8
g of 3-methylpicolinic acid, and the mixture was heated and
refluxed for 30 minutes. The reaction mixture was cooled, and
acetone was distilled off under reduced pressure. Water was added
to the residue, and extraction was then performed with ethyl
acetate. The organic layer was washed with water twice, and the
solvent was concentrated under reduced pressure. The obtained
residue was purified by silica gel column chromatography
(dichloromethane:methanol=20:1) to give 1.5 g of white powdery
N-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-methylpicolinamide-
.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.57 (1H, br s), 8.39 (1H, d,
J=7.5 Hz), 7.65-7.28 (10H, m), 6.94 (1H, d, J=9.0 Hz), 5.21 (2H,
s), 4.58 (2H, dd, J=5.7, 0.9 Hz), 3.93 (3H, s), 2.76 (3H, s)
Example 17
A 1.5 g quantity of the N-[2-(3-benzyloxy-4-methoxy
phenyl)oxazol-4-ylmethyl]-3-methylpicolinamide obtained in Example
16 was dissolved in 50 ml of ethanol, and 0.1 g of 10% palladium
carbon powder was added thereto. The mixture was stirred in a
hydrogen atmosphere at 50.degree. C. for two hours. The catalyst
was removed by filtration, and the filtrate was then concentrated
to give 1.3 g of white crystalline
N-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-methylpicolinamide.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.58 (1H, br s), 8.38 (1H, dd,
J=4.5, 0.9 Hz), 7.63 (1H, s), 7.62-7.54 (3H, m), 7.32-7.27 (1H, m),
6.90 (1H, d, J=8.4 Hz), 5.75 (1H, br s), 4.58 (2H, dd, J=6.0, 0.9
Hz), 3.94 (3H, s), 2.75 (3H, s)
Example 18
A 0.15 g quantity of the
N-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-methylpicolinamide
obtained in Example 17 and 0.5 ml of
1,8-diazabicyclo[5,4,0]undec-7-ene were dissolved in 4 ml of
ethanol, and 0.13 g of bromocyclopentane was added thereto. The
mixture was heated and refluxed for 3 hours. The reaction mixture
was allowed to cool, water was then added thereto, and extraction
was performed with ethyl acetate. The extract was washed with water
twice, and the organic layer was concentrated under reduced
pressure. The obtained residue was purified by silica gel column
chromatography (n-hexane:ethyl acetate=3:1) to give 0.11 g of white
powdery
N-[2-(3-cyclopentyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-methy-
lpicolinamide.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.57 (1H, br s), 8.39 (1H, dd,
J=4.8, 0.9 Hz), 7.62-7.53 (4H, m), 7.32-7.27 (1H, m), 6.91 (1H, d,
J=8.4 Hz), 4.88 (1H, tt, J=3.3 Hz), 4.59 (2H, dd, J=5.7, 0.9 Hz),
3.89 (3H, s), 2.76 (3H, s), 2.07-1.79 (6H, m), 1.70-1.60 (2H,
m)
Example 19
A 0.15 g quantity of the N-[2-(3-hydroxy-4-methoxy
phenyl)oxazol-4-ylmethyl]-3-methylpicolinamide obtained in Example
17 and 0.18 g of potassium carbonate were dissolved in 4 ml of
dimethylformamide, and 0.19 g of 1,1,1-trifluoro-2-iodoethane was
added thereto. The mixture was stirred with heating at 80.degree.
C. overnight. The reaction mixture was allowed to cool, water was
then added thereto, and extraction was performed with ethyl
acetate. The extract was washed with water twice, and the organic
layer was concentrated under reduced pressure. The obtained residue
was purified by silica gel column chromatography (n-hexane:ethyl
acetate=3:1) to give 0.11 g of white powdery
N-{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-ylmethyl-
}-3-methylpicolinamide.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.58 (1H, br s), 8.39 (1H, dd,
J=4.5, 1.2 Hz), 7.73 (1H, dd, J=8.7, 2.1 Hz), 7.63-7.57 (3H, m),
7.32-7.27 (1H, m), 6.97 (1H, d, J=8.4 Hz), 4.59 (2H, dd, J=5.7, 0.9
Hz), 4.46 (2H, q, J=8.4 Hz), 3.93 (3H, s), 2.76 (3H, s)
Example 20
Using 0.2 g of the
N-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-methylpicolinamide
obtained in Example 17, 0.11 g of
N-[2-(3-ethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-methylpicolinamide
was obtained in the same manner as in Example 3.
Colorless Crystals
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.57 (1H, br s), 8.39 (1H, dd,
J=4.8, 1.5 Hz), 7.65-7.50 (4H, m), 7.30 (1H, dd, J=7.8, 4.8 Hz),
6.92 (1H, d, J=8.1 Hz), 4.59 (1H, dd, J=6.0, 0.6 Hz), 4.19 (2H, q,
J=6.9 Hz), 4.17 (2H, q, J=6.9 Hz), 3.92 (3H, s), 2.76 (3H, s), 1.50
(3H, t, J=6.9 Hz)
Example 21
Using 0.15 g of the
N-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-methylpicolinamide
obtained in Example 17, 45 mg of
N-[2-(3-allyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-methylpicolinamide
was obtained in the same manner as in Example 3.
Colorless Crystal
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.58 (1H, br s), 8.39 (1H, dd,
J=4.5, 1.5 Hz), 7.65-7.50 (4H, m), 7.30 (1H, dd, J=7.8, 4.5 Hz),
6.93 (1H, d, J=8.4 Hz), 6.12 (1H, m), 5.45 (1H, m), 5.32 (1H, dd,
J=9.6, 1.5 Hz), 4.70 (2H, d, J=5.4 Hz), 4.59 (1H, d, J=6.0 Hz),
3.92 (3H, s), 2.76 (3H, s).
Example 22
A 170 mg quantity of the N-[2-(3-hydroxy-4-methoxy
phenyl)oxazol-4-ylmethyl]-3-methylpicolinamide obtained in Example
17 was dissolved in 10 ml of tetrahydrofuran. To the obtained
solution were added 134 mg of 2-hydroxyindane, 0.5 ml of
diisopropyl azodicarboxylate (40% toluene solution) and 202 mg of
tri(n-butyl)phosphine, and the mixture was stirred at room
temperature overnight, and at 50.degree. C. for 2.5 hours. To the
reaction mixture were added 100 mg of 2-hydroxyindane, 0.5 ml of
diisopropyl azodicarboxylate (40% toluene solution) and 200 mg of
tri(n-butyl)phosphine, and the mixture was stirred at 50.degree. C.
for 5 hours, and at room temperature overnight. The reaction
mixture was concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (n-hexane:ethyl
acetate:methylene chloride=1:1:1) to give 92 mg of
N-{2-[3-(indan-2-yloxy)-4-methoxyphenyl]oxazol-4-ylmethyl}-3-methylpicoli-
namide.
Pale Yellow Oily Substance
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.59 (1H, br s), 8.39 (1H, d,
J=3.3 Hz), 7.65-7.16 (9H, m), 6.93 (1H, d, J=8.1 Hz), 5.30 (1H, tt,
J=6.6, 3.9 Hz), 4.60 (2H, d, J=5.7 Hz), 3.86 (3H, s), 3.46 (2H, dd,
J=16.8, 6.6 Hz), 3.27 (2H, dd, J=16.8, 3.9 Hz), 2.76 (3H, s)
Example 23
Using 0.88 g of the
[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-yl]methylamine obtained in
Reference Example 7, 1.03 g of white powdery
N-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-trifluoromethylben-
zamide was obtained in the same manner as in Example 1.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.72-7.46 (9H, m), 7.40-7.27 (3H,
m), 6.95 (1H, d, J=8.4 Hz) 6.34 (1H, br s), 5.20 (2H, s), 4.59 (2H,
d, J=5.4 Hz), 3.93 (3H, s)
Example 24
Using 1.0 g of the
N-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-trifluoromethylben-
zamide obtained in Example 23, 0.66 g of white powdery
N-[2-(3-hydroxy-4-methoxyphenyl)
oxazol-4-ylmethyl]-2-trifluoromethylbenzamide was obtained in the
same manner as in Example 2.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.71-7.50 (7H, m), 6.90 (1H, d,
J=8.4 Hz), 6.39 (1H, br s), 5.76 (1H, s), 4.59 (2H, d, J=5.4 Hz),
3.94 (3H, s)
Example 25
Using 0.2 g of the
N-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-trifluoromethylbenza-
mide obtained in Example 24, 0.18 g of white powdery
N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-trifluoro-
methylbenzamide was obtained in the same manner as in Example
3.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.72-7.50 (7H, m), 6.93 (1H, d,
J=8.4 Hz), 6.34 (1H, s), 4.60 (2H, d, J=5.4 Hz), 3.93 (3H, s),
1.42-1.32 (1H, m), 0.70-0.63 (2H, m), 0.41-0.35 (2H, m)
Example 26
Using 0.2 g of the
N-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-trifluoromethylbenza-
mide obtained in Example 24, 40 mg of white powdery
N-{2-[3-(3-hydroxypropoxy)-4-methoxyphenyl]oxazol-4-ylmethyl}-2-trifluoro-
methylbenzamide was obtained in the same manner as in Example
3.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.71-7.50 (7H, m), 6.92 (1H, d,
J=8.4 Hz), 6.34 (1H, br s), 4.60 (2H, d, J=5.4 Hz), 4.28 (2H, q,
J=5.7 Hz), 3.98-3.86 (5H, m), 2.47 (1H, t, J=5.7 Hz), 2.15-2.07
(3H, m)
Example 27
Using 0.5 g of the
2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-yl]methylamine obtained in
Reference Example 7, 0.62 g of white powdery
N-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-ethoxypicolinamide
was obtained in the same manner as in Example 1.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.24-8.22 (2H, m), 7.64-7.60 (3H,
m), 7.50-7.46 (2H, m), 7.41-7.28 (5H, m), 6.94 (1H, d, J=9.0 Hz),
5.20 (2H, s), 4.61 (2H, d, J=5.7 Hz), 4.17 (2H, q, J=6.9 Hz), 3.93
(3H, s), 1.50 (3H, t, J=6.9 Hz)
Example 28
Using 0.6 g of the
N-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-ethoxypicolinamide
obtained in Example 27, 0.5 g of white amorphous
N-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-ethoxypicolinamide
was obtained in the same manner as in Example 2.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.25-8.22 (2H, m), 7.64 (1H, d,
J=1.8 Hz), 7.60-7.54 (2H, m), 7.39-7.28 (2H, m), 6.91 (1H, d, J=8.1
Hz), 5.71 (1H, br s), 4.61 (2H, dd, J=5.4, 0.9 Hz), 4.17 (2H, q,
J=6.9 Hz), 3.94 (3H, s), 1.52 (3H, t, J=6.9 Hz)
Example 29
Using 0.5 g of the
N-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-ethoxypicolinamide
obtained in Example 28, 0.18 g of white amorphous
N-[2-(3-cyclopentyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-ethoxypicolin-
amide was obtained in the same manner as in Example 3.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.25-8.22 (2H, m), 7.64 (1H, s),
7.58 (1H, dd, J=8.4, 2.1 Hz), 7.53 (1H, d, J=1.8 Hz), 7.39-7.32
(2H, m), 6.91 (1H, d, J=8.4 Hz), 4.91-4.86 (1H, m), 4.62 (2H, dd,
J=5.4, 0.9 Hz), 4.17 (2H, q, J=6.9 Hz), 3.89 (3H, s), 2.05-1.79
(6H, m), 1.66-1.60 (2H, m), 1.51 (3H, t, J=6.9 Hz)
Example 30
Using 0.31 g of the
2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-yl]methylamine obtained in
Reference Example 7, 0.16 g of white powdery
N-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-(2,2,2-trifluoroet-
hoxy)benzamide was obtained in the same manner as in Example 1.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.22 (1H, dd, J=7.8, 1.8 Hz),
7.82 (1H, br s), 7.63-7.60 (3H, m), 7.49-7.27 (6H, m), 7.19 (1H, t,
J=7.2 Hz), 6.96-6.88 (2H, m), 5.19 (2H, s), 4.62 (2H, d, J=5.4 Hz),
4.47 (2H, q, J=7.8 Hz), 3.92 (3H, s)
Example 31
Using 0.16 g of the
N-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-(2,2,2-trifluoroet-
hoxy)benzamide obtained in Example 30, 0.11 g of white powdery
N-[2-(3-hydroxy-4-methoxy
phenyl)oxazol-4-ylmethyl]-2-(2,2,2-trifluoroethoxy)benzamide was
obtained in the same manner as in Example 2.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.21 (1H, dd, J=7.8, 1.8 Hz),
7.84 (1H, br s), 7.62-7.54 (3H, m), 7.49-7.43 (1H, m), 7.19 (1H,
td, J=7.8, 0.9 Hz), 5.71 (1H, s), 4.62 (2H, dd, J=5.4, 0.9 Hz),
4.48 (2H, q, J=7.8 Hz), 3.94 (3H, s)
Example 32
Using 0.11 g of the
N-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-(2,2,2-trifluoroetho-
xy)benzamide obtained in Example 31, 78 mg of white amorphous
N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-(2,2,2-tr-
ifluoroethoxy)benzamide was obtained in the same manner as in
Example 3.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.22 (1H, dd, J=7.8, 2.1 Hz),
7.83 (1H, br s), 7.61-7.57 (3H, m), 7.53 (1H, d, J=2.1 Hz),
7.50-7.43 (1H, m), 7.19 (1H, td, J=7.8, 0.9 Hz), 6.94-6.88 (2H, m),
4.63 (2H, dd, J=5.4, 0.9 Hz), 4.48 (2H, q, J=7.8 Hz), 1.42-1.32
(1H, m), 0.70-0.63 (2H, m), 0.41-0.35 (2H, m)
Example 33
Using 0.5 g of the
2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-yl]methylamine obtained in
Reference Example 7, 0.68 g of pale yellow powdery
N-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-methoxybenzamide
was obtained in the same manner as in Example 1.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.39 (1H, br s), 8.23 (1H, dd,
J=4.8, 1.8 Hz), 7.65-7.60 (3H, m), 7.50-7.28 (6H, m), 7.08 (1H, t,
J=7.2 Hz), 6.98-6.93 (2H, m), 5.21 (2H, s), 4.61 (2H, dd, J=5.4,
0.9 Hz), 3.95 (3H, s), 3.93 (3H, s)
Example 34
Using 0.67 g of the
N-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-methoxybenzamide
obtained in Example 33, 0.52 g of white amorphous
N-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-methoxybenzamide
was obtained in the same manner as in Example 2.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.43 (1H, br s), 8.23 (1H, dd,
J=7.8, 2.1 Hz), 7.63 (1H, s), 7.60-7.54 (2H, m), 7.47-7.41 (1H, m),
7.10-7.05 (1H, m), 6.97 (1H, d, J=8.4 Hz), 6.91 (1H, d, J=8.1 Hz),
5.74 (1H, br s), 4.62 (2H, dd, J=5.4, 0.9 Hz), 3.97 (3H, s), 3.95
(3H, s)
Example 35
Using 0.5 g of the
N-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-methoxybenzamide
obtained in Example 34, 0.39 g of white powdery
N-[2-(3-cyclopentyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-methoxybenzam-
ide was obtained in the same manner as in Example 3.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.41 (1H, br s), 8.23 (1H, dd,
J=7.8, 1.8 Hz), 7.63 (1H, s), 7.59 (1H, dd, J=8.4, 1.8 Hz), 7.54
(1H, d, J=1.8 Hz), 7.48-7.42 (1H, m), 7.08 (1H, t, J=7.8 Hz), 6.98
(1H, d, J=8.1 Hz), 6.92 (1H, d, J=8.4 Hz), 4.91-4.87 (1H, m), 4.62
(2H, dd, J=5.4, 0.9 Hz), 3.97 (3H, s), 3.90 (3H, s), 2.05-1.80 (6H,
m), 1.66-1.59 (2H, m)
Example 36
A 0.2 g quantity of the
[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-yl]methylamine
obtained in Reference Example 13 was suspended in 4 ml of acetone.
To the obtained suspension were added 0.2 g of
1-hydroxybenzotriazole, 0.29 g of
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and
0.14 g of 3-methylpicolinic acid, and the mixture was heated and
refluxed for 30 minutes. The reaction mixture was cooled, water was
then added thereto, and extraction was performed with ethyl
acetate. The organic layer was washed with water twice, and the
solvent was concentrated under reduced pressure. The obtained
residue was purified by silica gel column chromatography
(n-hexane:ethyl acetate=1:1) to give 0.16 g of white powdery
N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-m-
ethylpicolinamide.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.58 (1H, br s) 8.39 (1H, dd,
J=4.5, 1.2 Hz), 7.63-7.57 (3H, m), 7.52 (1H, d, J=2.1 Hz),
7.33-7.28 (1H, m), 6.92 (1H, d, J=8.4 Hz), 4.59 (2H, dd, J=6.0, 0.9
Hz), 3.97-3.90 (5H, m), 2.76 (3H, s), 1.41-1.31 (1H, m), 0.70-0.63
(2H, m), 0.41-0.35 (2H, m)
Using 0.2 g of the [2-(3-cyclopropylmethoxy-4-methoxy
phenyl)oxazol-4-yl]methylamine obtained in Reference Example 13,
compounds of Examples 37 to 43 were obtained in the same manner as
in Example 1.
Example 37
N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-isopropoxy-
benzamide
Yield 0.17 g
White Powder
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.62 (1H, br s) 8.23 (1H, dd,
J=7.8, 1.8 Hz), 7.62-7.58 (2H, m), 7.54 (1H, d, J=2.1 Hz),
7.43-7.38 (1H, m), 7.05 (1H, td, J=8.1, 0.9 Hz), 6.97-6.91 (2H, m),
4.76-4.67 (1H, m), 4.61 (2H, dd, J=5.4, 0.9 Hz), 3.94-3.90 (5H, m),
1.41-1.38 (7H, m), 0.69-0.64 (2H, m), 0.41-0.35 (2H, m)
Example 38
N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-methylbenz-
amide
Yield 0.16 g
White Powder
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.64 (1H, s) 7.59 (1H, dd, J=8.4,
2.1 Hz), 7.50 (1H, d, J=2.1 Hz), 7.41-7.16 (3H, m), 6.93 (1H, d,
J=8.4 Hz), 6.31 (1H, br s), 4.58 (2H, dd, J=5.4, 0.9 Hz), 3.95-3.92
(5H, m), 2.46 (3H, s), 1.42-1.32 (1H, m), 0.70-0.63 (2H, m),
0.41-0.35 (2H, m)
Example 39
N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-ethylbenza-
mide
Yield 0.15 g
White Powder
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.64 (1H, s) 7.59 (1H, dd, J=8.4,
2.1 Hz), 7.50 (1H, d, J=1.8 Hz), 7.41-7.16 (3H, m), 6.93 (1H, d,
J=8.1 Hz), 6.31 (1H, br s), 4.57 (2H, d, J=5.4 Hz), 3.95-3.92 (5H,
m), 2.81 (2H, q, J=7.5 Hz), 1.42-1.32 (1H, m), 1.23 (3H, t, J=7.5
Hz), 0.70-0.63 (2H, m), 0.41-0.35 (2H, m)
Example 40
N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-chlorobenz-
amide
Yield 0.17 g
White Powder
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.71-7.66 (2H, m), 7.59 (1H, dd,
J=8.4, 1.8 Hz), 7.50 (1H, d, J=2.1 Hz), 7.42-7.29 (3H, m), 6.93
(1H, d, J=8.4 Hz), 6.75 (1H, br s), 4.62 (2H, dd, J=5.4, 0.9 Hz),
3.95-3.92 (5H, m), 1.41-1.32 (1H, m), 0.70-0.63 (2H, m), 0.41-0.35
(2H, m)
Example 41
N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-5-fluoro-2-m-
ethoxybenzamide
Yield 0.19 g
White Powder
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.45 (1H, br s), 7.94 (1H, dd,
J=9.6, 3.3 Hz), 7.63 (1H, s), 7.61 (1H, dd, J=8.1, 1.8 Hz), 7.51
(1H, d, J=1.8 Hz), 7.17-7.10 (1H, m), 6.95-6.90 (2H, m), 4.61 (2H,
d, J=5.4 Hz), 3.96-3.92 (8H, m), 1.40-1.30 (1H, m), 0.70-0.64 (2H,
m), 0.41-0.35 (2H, m)
Example 42
N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-4-fluoro-2-m-
ethoxybenzamide
Yield 0.19 g
White Powder
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.27-8.21 (2H, m), 7.63-7.58 (2H,
m), 7.52 (1H, d, J=2.1 Hz), 6.93 (1H, d, J=8.4 Hz), 6.81-6.74 (1H,
m), 6.69 (1H, dd, J=10.2, 2.1 Hz), 4.60 (2H, dd, J=5.4, 0.9 Hz),
3.97-3.90 (8H, m), 1.40-1.30 (1H, m), 0.70-0.64 (2H, m), 0.41-0.35
(2H, m)
Example 43
N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-fluoro-6-m-
ethoxybenzamide
Yield 0.17 g
White Powder
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.65 (1H, s), 7.59 (1H, dd,
J=8.4, 2.1 Hz), 7.50 (1H, d, J=2.1 Hz), 7.34-7.27 (1H, m), 6.92
(1H, d, J=8.4 Hz), 6.76-6.70 (2H, m), 6.51 (1H, br s), 4.61 (2H, d,
J=5.7 Hz), 3.94-3.91 (5H, m), 3.85 (3H, s), 1.42-1.31 (1H, m),
0.70-0.63 (2H, m), 0.41-0.35 (2H, m)
Example 44
Using 0.4 g of the [2-(3-cyclopropylmethoxy-4-methoxy
phenyl)oxazol-4-yl]methylamine obtained in Reference Example 13,
N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-methylsul-
fanylbenzamide was obtained in the same manner as in Example 1.
Yield 0.4 g
White Powder
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.68 (1H, s), 7.61-7.56 (2H, m),
7.50 (1H, d, J=1.8 Hz), 7.34-7.17 (3H, m), 6.95-6.90 (2H, m), 4.61
(2H, dd, J=5.4, 0.9 Hz), 3.95-3.92 (5H, m), 2.46 (3H, s), 1.42-1.31
(1H, m), 0.70-0.63 (2H, m), 0.41-0.35 (2H, m)
Example 45
Using 0.7 g of the [2-(3-cyclopropylmethoxy-4-methoxy
phenyl)oxazol-4-yl]methylamine obtained in Reference Example 13,
N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-hydroxypi-
colinamide was obtained in the same manner as in Example 1.
Yield 0.6 g
White Powder
.sup.1H-NMR (CDCl.sub.3) .delta.: 12.02 (1H, s), 8.45 (1H, br s),
8.06 (1H, dd, J=4.2, 1.8 Hz), 7.63-7.59 (2H, m), 7.52 (1H, s),
7.37-7.29 (3H, m), 6.93 (1H, d, J=8.4 Hz), 4.60 (2H, d, J=6.0 Hz),
3.96-3.93 (5H, m), 1.56-1.33 (1H, m), 0.70-0.64 (2H, m), 0.42-0.36
(2H, m)
Using 0.1 g of the [2-(3-cyclopropylmethoxy-4-methoxy
phenyl)oxazol-4-yl]methylamine obtained in Reference Example 13,
compounds of Examples 46 to 56 were obtained in the same manner as
in Example 1.
Example 46
N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-methoxyben-
zamide
Yield 0.1 g
White Powder
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.40 (1H, br s), 8.23 (1H, dd,
J=7.8, 2.1 Hz) 7.64-7.58 (2H, m), 7.52 (1H, d, J=2.1 Hz), 7.48-7.42
(1H, m), 7.08 (1H, td, J=7.8, 0.9 Hz), 6.99-6.91 (2H, m), 4.62 (2H,
dd, J=5.4, 0.9 Hz), 3.97-3.91 (8H, m), 1.40-1.32 (1H, m), 0.70-0.63
(2H, m), 0.41-0.35 (2H, m)
Example 47
N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-trifluorom-
ethoxybenzamide
Yield 43 mg
White Powder
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.02 (1H, dd, J=7.8, 1.8 Hz),
7.64-7.27 (6H, m), 7.10 (1H, br s), 6.93 (1H, d, J=8.4 Hz), 4.62
(2H, dd, J=5.4, 0.9 Hz), 3.95-3.92 (5H, m), 1.43-1.28 (1H, m),
0.69-0.63 (2H, m), 0.41-0.36 (2H, m)
Example 48
N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-propoxyben-
zamide
Yield 0.1 g
White Powder
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.50 (1H, br s), 8.24 (1H, dd,
J=7.8, 1.8 Hz) 7.61-7.58 (2H, m), 7.53 (1H, d, J=1.8 Hz), 7.44-7.38
(1H, m), 7.06 (1H, t, J=7.8 Hz), 6.95-6.91 (2H, m), 4.62 (2H, d,
J=5.1 Hz), 4.06 (2H, t, J=6.6 Hz), 3.95-3.68 (5H, m), 1.86 (2H, td,
J=7.5, 6.6 Hz), 1.41-1.31 (1H, m), 0.96 (3H, t, J=7.5 Hz),
0.70-0.61 (2H, m), 0.41-0.35 (2H, m)
Example 49
N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]pyrazine-2-ca-
rboxamide
Yield 90 mg
White Powder
.sup.1H-NMR (CDCl.sub.3) .delta.: 9.42 (1H, s), 8.75 (1H, d, J=2.4
Hz), 8.52 (1H, dd, J=2.7, 1.5 Hz), 8.25 (1H, br s), 7.64 (1H, s),
7.60 (1H, dd, J=8.4, 1.8 Hz), 7.52 (1H, d, J=1.8 Hz), 6.92 (1H, d,
J=8.4 Hz), 4.63 (2H, dd, J=5.4, 0.9 Hz), 4.11-3.92 (5H, m),
1.40-1.32 (1H, m), 0.70-0.63 (2H, m), 0.41-0.35 (2H, m)
Example 50
N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-ethoxypico-
linamide
Yield 85 mg
White Powder
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.24-8.22 (2H, m) 7.64 (1H, s),
7.60 (1H, dd, J=8.4, 1.8 Hz), 7.51 (1H, d, J=2.1 Hz), 7.39-7.32
(2H, m), 6.92 (1H, d, J=8.4 Hz), 4.62 (2H, dd, J=5.4, 0.9 Hz), 4.17
(2H, q, J=6.9 Hz), 3.98-3.92 (5H, m), 1.52 (3H, t, J=6.9 Hz),
1.43-1.32 (1H, m), 0.71-0.63 (2H, m), 0.41-0.35 (2H, m)
Example 51
N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-butoxybenz-
amide
Yield 70 mg
White Powder
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.48 (1H, br s) 8.23 (1H, dd,
J=7.8, 1.8 Hz), 7.63-7.59 (2H, m), 7.53 (1H, d, J=2.1 Hz),
7.45-7.38 (1H, m), 7.06 (1H, td, J=8.4, 0.9 Hz), 6.96-6.91 (2H, m),
4.61 (2H, d, J=5.1 Hz), 4.09 (2H, t, J=6.6 Hz), 3.94-3.91 (5H, m),
1.84-1.75 (2H, m), 1.46-1.33 (3H, m), 0.84 (3H, t, J=7.2 Hz),
0.70-0.63 (2H, m), 0.41-0.35 (2H, m)
Example 52
N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-isobutoxyb-
enzamide
Yield 0.12 g
White Powder
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.46 (1H, br s) 8.24 (1H, dd,
J=7.8, 1.8 Hz), 7.62-7.58 (2H, m), 7.52 (1H, d, J=1.8 Hz), 7.41
(1H, t, J=7.2 Hz), 7.06 (1H, t, J=7.2 Hz), 6.95-6.91 (2H, m), 4.62
(2H, d, J=5.1 Hz), 3.95-3.92 (5H, m), 3.86 (2H, d, J=6.3 Hz),
2.20-2.10 (1H, m), 1.40-1.31 (1H, m), 0.95 (6H, d, J=6.6 Hz),
0.70-0.63 (2H, m), 0.41-0.37 (2H, m)
Example 53
N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-isopropoxy-
picolinamide
Yield 0.1 g
White Powder
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.28-8.25 (2H, m) 7.63 (1H, s),
7.60 (1H, dd, J=8.4, 2.1 Hz), 7.52 (1H, d, J=2.1 Hz), 7.38-7.31
(2H, m), 6.93 (1H, d, J=8.4 Hz), 4.70-4.61 (3H, m), 3.98-3.90 (5H,
m), 1.42-1.31 (7H, m), 0.70-0.61 (2H, m), 0.41-0.35 (2H, m)
Example 54
N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-ethylsulfa-
nylbenzamide
Yield 85 mg
White Powder
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.70-7.66 (2H, m), 7.59 (1H, dd,
J=8.4, 1.8 Hz), 7.51 (1H, d, J=2.1 Hz), 7.43-7.32 (2H, m),
7.27-7.22 (2H, m), 6.92 (1H, d, J=8.7 Hz), 4.61 (2H, dd, J=5.4, 0.6
Hz), 3.95-3.92 (5H, m), 2.90 (2H, q, J=7.5 Hz), 1.40-1.34 (1H, m),
1.26 (3H, t, J=7.2 Hz), 0.70-0.63 (2H, m), 0.41-0.35 (2H, m)
Example 55
N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-1-oxidepicol-
inamide
Yield 53 mg
Pale Yellow Powder
.sup.1H-NMR (CDCl.sub.3) .delta.: 11.64 (1H, br s), 8.44 (1H, dd,
J=7.8, 2.1 Hz), 8.25 (1H, d, J=6.3 Hz), 7.63-7.35 (5H, m), 6.91
(1H, d, J=8.7 Hz), 4.65 (2H, d, J=5.7 Hz), 3.97-3.88 (5H, m),
1.43-1.32 (1H, m), 0.70-0.63 (2H, m), 0.41-0.36 (2H, m)
Example 56
N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2,6-dimethox-
ybenzamide
Yield 46 mg
White Powder
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.67 (1H, s), 7.59 (1H, dd,
J=8.4, 1.8 Hz), 7.50 (1H, d, J=2.1 Hz), 7.30-7.24 (1H, m), 6.92
(1H, d, J=8.4 Hz), 6.56 (2H, d, J=8.4 Hz), 6.24 (1H, br s), 4.62
(2H, dd, J=5.7, 0.9 Hz), 3.95-3.92 (5H, m), 3.81 (6H, s), 1.41-1.32
(1H, m), 0.70-0.63 (2H, m), 0.41-0.35 (2H, m)
Using 0.13 g of [2-(3-cyclopropylmethoxy-4-methoxy
phenyl)oxazol-4-yl]methylamine, compounds of Examples 57 to 59 were
obtained in the same manner as in Example 1.
Example 57
N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-methoxypic-
olinamide
Yield 24 mg
White Powder
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.23-8.19 (2H, m) 7.65 (1H, s),
7.59 (1H, dd, J=8.4, 2.1 Hz), 7.51 (1H, d, J=1.8 Hz), 7.43-7.34
(2H, m), 6.92 (1H, d, J=8.7 Hz), 4.60 (2H, d, J=5.4 Hz), 3.96-3.93
(8H, m), 1.43-1.30 (1H, m), 0.70-0.63 (2H, m), 0.41-0.35 (2H,
m)
Example 58
N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-isobutoxyp-
icolinamide
Yield 0.11 g
White Powder
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.24 (1H, dd, J=3.9, 1.8 Hz),
8.17 (1H, br s), 7.63 (1H, s), 7.59 (1H, dd, J=8.4, 1.8 Hz),
7.38-7.31 (2H, m), 6.92 (1H, d, J=8.4 Hz), 4.62 (2H, dd, J=5.4, 0.9
Hz), 3.95-3.92 (5H, m), 3.84 (2H, d, J=6.3 Hz), 2.20 (1H, qt, J=6.6
Hz), 1.40-1.34 (1H, m), 1.03 (6H, d, J=6.6 Hz), 0.70-0.63 (2H, m),
0.41-0.35 (2H, m)
Example 59
N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-methylnico-
tinamide
Yield 71 mg
White Powder
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.55 (1H, dd, J=7.8, 1.8 Hz),
7.71 (1H, dd, J=7.5, 1.8 Hz), 7.65 (1H, s), 7.59 (1H, dd, J=8.4,
2.1 Hz), 7.17-7.13 (1H, m), 6.93 (2H, d, J=8.4 Hz), 6.35 (1H, br
s), 4.58 (2H, dd, J=5.4, 0.9 Hz), 3.96-3.91 (5H, m), 2.69 (3H, s),
1.41-1.31 (1H, m), 0.70-0.63 (2H, m), 0.41-0.35 (2H, m)
Example 60
0.4 g of
N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2--
methylsulfanylbenzamide obtained in Example 44 was dissolved in 20
ml of dichloromethane, and 0.67 g of metachloroperbenzoic acid was
added thereto while the solution was cooled with ice with stirring.
The mixture was then stirred for an hour. The reaction mixture was
concentrated under reduced pressure, the residue was purified by
silica gel column chromatography (NH silica, n-hexane:ethyl
acetate=1:1), and 50 mg of white powdery
N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)
oxazol-4-ylmethyl]-2-methanesulfonylbenzamide was obtained.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.11 (1H, dd, J=7.8, 0.9 Hz),
7.76 (1H, s), 7.69-7.55 (4H, m), 7.50 (1H, d, J=2.1 Hz), 6.93 (1H,
d, J=8.4 Hz), 6.50 (1H, br s), 4.62 (2H, d, J=5.4 Hz), 3.95-3.90
(5H, m), 3.93-3.67 (1H, m), 3.37 (3H, s), 1.40-1.32 (1H, m),
1.27-1.18 (3H, m), 0.70-0.63 (2H, m), 0.41-0.35 (2H, m)
Example 61
0.1 g of
N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3--
hydroxypicolinamide obtained in Example 45 and 0.16 g of cesium
carbonate were dissolved in 4 ml of acetonitrile, and 0.2 g of
1-bromopropane was added thereto and stirred overnight at room
temperature. Water was added to the reaction mixture and extraction
was performed with ethyl acetate. The extract was washed with water
once, and further washed with saturated aqueous citric acid once.
The organic layer was concentrated under reduced pressure, and the
obtained residue was purified by silica gel column chromatography,
yielding 72 mg of white powdery
N-2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-propoxypic-
olinamide.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.25-8.20 (2H, m) 7.64 (1H, s),
7.60 (1H, dd, J=8.4, 1.8 Hz), 7.52 (1H, d, J=1.8 Hz), 7.39-7.32
(2H, m), 6.92 (1H, d, J=8.4 Hz), 4.62 (2H, dd, J=5.7, 0.9 Hz), 4.05
(2H, t, J=6.6 Hz), 3.94-3.92 (5H, m), 1.90 (2H, t, J=7.5, 6.6 Hz),
1.40-1.33 (1H, m), 1.04 (3H, t, J=7.5 Hz), 0.70-0.63 (2H, m),
0.41-0.35 (2H, m)
Example 62
Using 0.18 g of
[2-(3-isobutoxy-4-methoxyphenyl)oxazol-4-yl]methylamine obtained in
Reference Example 19, 0.16 g of white powdery
N-[2-(3-isobutoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-methylpicolinamide
was obtained in the same manner as in Example 1.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.58 (1H, br s) 8.39 (1H, dd,
J=4.5, 1.8 Hz), 7.63 (1H, s), 7.62-7.59 (2H, m), 7.57 (1H, d, J=0.9
Hz), 7.32-7.27 (1H, m), 6.92 (1H, d, J=8.4 Hz), 4.59 (2H, dd,
J=6.0, 0.9 Hz), 3.91 (3H, s), 3.86 (2H, d, J=6.9 Hz), 2.76 (3H, s),
2.20 (1H, qt, J=6.9, 6.6 Hz), 1.06 (6H, d, J=6.6 Hz)
Using 0.15 g of
[2-(3-isobutoxy-4-methoxyphenyl)oxazol-4-yl]methylamine obtained in
Reference Example 19, compounds of Examples 63 to 75 were obtained
in the same manner as in Example 1.
Example 63
N-[2-(3-isobutoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-methoxybenzamide
Yield 0.12 g
White Powder
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.41 (1H, br s) 8.23 (1H, dd,
J=7.8, 1.8 Hz), 7.64 (1H, s), 7.59 (1H, dd, J=8.4, 2.1 Hz), 7.53
(1H, d, J=2.1 Hz), 7.48-7.42 (1H, m), 7.11-6.90 (3H, m), 4.63 (2H,
dd, J=5.4, 0.9 Hz), 3.97 (3H, s), 3.91 (3H, s), 3.86 (2H, d, J=6.9
Hz), 2.21 (1H, qt, J=6.6 Hz), 1.06 (6H, d, J=6.6 Hz)
Example 64
N-[2-(3-isobutoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-methyl
sulfanylbenzamide
Yield 0.15 g
White Powder
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.69 (1H, s), 7.61-7.56 (2H, m),
7.51 (1H, d, J=1.8 Hz), 7.45-7.15 (3H, m) 6.94-6.90 (2H, m), 4.61
(2H, d, J=5.7 Hz), 3.91 (3H, s), 3.85 (2H, d, J=6.9 Hz), 2.46 (3H,
s), 2.20 (1H, qt, J=6.9 Hz), 1.06 (6H, d, J=6.9 Hz)
Example 65
N-[2-(3-isobutoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-ethoxy
picolinamide
Yield 80 mg
White Powder
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.25-8.22 (2H, m) 7.65 (1H, s),
7.58 (1H, dd, J=8.4, 1.8 Hz), 7.52 (1H, d, J=1.8 Hz), 7.40-7.32
(2H, m), 6.92 (1H, d, J=8.4 Hz), 4.62 (2H, dd, J=5.4, 0.9 Hz), 4.18
(2H, q, J=6.9 Hz), 3.91 (3H, s), 3.86 (2H, d, J=6.9 Hz), 2.20 (1H,
qt, J=6.9 Hz), 1.52 (3H, t, J=6.9 Hz), 1.06 (6H, d, J=6.6 Hz)
Example 66
N-[2-(3-isobutoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-methoxy-4-fluoroben-
zamide
Yield 0.11 g
White Powder
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.27-8.21 (2H, m), 7.63 (1H, s),
7.59 (1H, dc, J=8.4, 2.1 Hz), 7.52 (1H, d, J=2.1 Hz), 6.93 (1H, d,
J=8.4 Hz), 6.81-6.74 (1H, m), 6.69 (1H, dd, J=10.5, 2.4 Hz), 4.61
(2H, dd, J=5.4, 0.9 Hz), 3.96 (3H, s), 3.91 (3H, s), 3.85 (2H, d,
J=6.6 Hz), 2.20 (1H, qt, J=6.9, 6.6 Hz), 1.06 (6H, d, J=6.6 Hz)
Example 67
N-[2-(3-isobutoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-isopropoxy
benzamide
Yield 0.15 g
Colorless Oily Substance
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.64 (1H, br s) 8.24 (1H, dd,
J=7.8, 1.8 Hz), 7.62-7.57 (2H, m), 7.54 (1H, d, J=1.8 Hz),
7.44-7.37 (1H, m), 7.08-7.02 (1H, m), 6.98-6.91 (2H, m), 4.72 (1H,
q, J=6.0 Hz), 4.62 (2H, dd, J=5.1, 0.9 Hz), 3.92 (3H, s), 3.85 (2H,
d, J=6.6 Hz), 2.20 (1H, qt, J=6.6 Hz), 1.40 (6H, d, J=6.0 Hz), 1.06
(6H, d, J=6.6 Hz)
Example 68
N-[2-(3-isobutoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-fluoro-6-methoxyben-
zamide
Yield 0.13 g
White Powder
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.65 (1H, d, J=0.9 Hz), 7.58 (1H,
dd, J=8.4, 2.1 Hz), 7.51 (1H, d, J=2.1 Hz), 7.34-7.24 (1H, m), 6.92
(1H, d, J=8.4 Hz), 6.77-6.70 (2H, m), 6.52 (1H, br s), 4.62 (2H,
dd, J=5.7, 0.9 Hz), 3.91 (3H, s), 3.90-3.82 (5H, m), 2.20 (1H, qt,
J=6.9 Hz), 1.06 (6H, d, J=6.9 Hz)
Example 69
N-[2-(3-isobutoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-methoxy
picolinamide
Yield 0.14 g
White Powder
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.19-8.22 (2H, m), 7.65 (1H, s),
7.58 (1H, dd, J=8.4, 1.8 Hz), 7.52 (1H, d, J=2.1 Hz), 7.43-7.34
(1H, m), 6.92 (1H, d, J=8.4 Hz), 4.61 (2H, dd, J=5.7, 0.9 Hz), 3.96
(3H, s), 3.91 (3H, s), 3.86 (2H, d, J=6.6 Hz), 2.20 (1H, qt, J=6.9,
6.6 Hz), 1.06 (6H, d, J=6.9 Hz)
Example 70
N-[2-(3-isobutoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-isobutoxy
picolinamide
Yield 68 mg
White Powder
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.24 (1H, dd, J=3.9, 2.1 Hz),
8.17 (1H, br s), 7.64 (1H, s), 7.58 (1H, dd, J=8.4, 2.1 Hz), 7.52
(1H, d, J=1.8 Hz), 7.38-7.28 (2H, m), 6.92 (2H, d, J=8.4 Hz), 4.63
(2H, dd, J=5.4, 0.9 Hz), 3.91 (3H, s), 3.87-3.82 (4H, m), 2.27-2.13
(2H, m), 1.07-1.02 (2H, m)
Example 71
N-[2-(3-isobutoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-propoxy
benzamide
Yield 75 mg
White Powder
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.52 (1H, br s), 8.23 (1H, dd,
J=7.8, 1.8 Hz), 7.62-7.58 (2H, m), 7.53 (1H, s), 7.42 (1H, td,
J=7.2, 1.8 Hz), 7.06 (1H, t, J=7.8 Hz), 6.95-6.91 (2H, m), 4.62
(2H, d, J=5.1 Hz), 4.06 (2H, t, J=6.6 Hz), 3.94 (3H, s), 3.85 (2H,
d, J=6.6 Hz), 2.24-2.16 (1H, m), 1.93-1.81 (2H, m), 1.06 (6H, d,
J=6.6 Hz), 0.97 (3H, t, J=7.2 Hz)
Example 72
N-[2-(3-isobutoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-butoxy
benzamide
Yield 47 mg
White Powder
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.48 (1H, br s), 8.23 (1H, dd,
J=7.8, 1.8 Hz), 7.62-7.58 (2H, m), 7.53 (1H, s), 7.42 (1H, td,
J=7.2, 1.8 Hz), 7.06 (1H, t, J=7.8 Hz), 6.95-6.91 (2H, m), 4.61
(2H, d, J=5.1 Hz), 4.10 (2H, t, J=6.6 Hz), 3.91 (3H, s), 3.85 (2H,
d, J=6.6 Hz), 2.24-2.16 (1H, m), 1.85-1.75 (2H, m), 1.43-1.36 (2H,
m), 1.05 (6H, d, J=6.6 Hz), 0.84 (3H, t, J=7.2 Hz)
Example 73
N-[2-(3-isobutoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-isobutoxy
benzamide
Yield 90 mg
White Powder
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.52 (1H, br s), 8.23 (1H, dd,
J=7.8, 1.8 Hz), 7.62-7.58 (2H, m), 7.53 (1H, s), 7.42 (1H, td,
J=7.2, 1.8 Hz), 7.06 (1H, t, J=7.8 Hz), 6.93-6.90 (2H, m), 4.62
(2H, d, J=5.1 Hz), 3.91 (3H, s), 3.87-3.83 (4H, m), 2.24-2.16 (2H,
m), 1.06 (6H, d, J=6.6 Hz), 0.95 (6H, d, J=6.6 Hz)
Example 74
N-[2-(3-isobutoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-isopropoxy
picolinamide
Yield 0.11 g
White Powder
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.52 (1H, br s), 8.27 (1H, br s),
7.63 (1H, s), 7.58 (1H, dd, J=7.8, 1.8 Hz), 7.53 (1H, s), 7.35-7.34
(2H, m), 6.92 (1H, d, J=8.4 Hz), 4.67-4.61 (3H, m), 3.91 (3H, s),
3.85 (2H, d, J=6.6 Hz), 2.22-2.17 (1H, m), 1.42 (6H, d, J=6.6 Hz),
1.06 (6H, d, J=6.6 Hz)
Example 75
N-[2-(3-isobutoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-methyl
nicotineamide
Yield 0.13 g
White Powder
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.52 (1H, br s), 7.86 (1H, d,
J=7.5 Hz), 7.76 (1H, d, J=7.5 Hz), 7.69 (1H, s), 7.59 (1H, d, J=4.2
Hz), 7.56 (1H, s), 6.92 (1H, d, J=8.7 Hz), 4.58 (2H, d, J=5.1 Hz),
3.91 (3H, s), 3.84 (2H, d, J=6.9 Hz), 2.69 (3H, s), 2.23-2.15 (1H,
m), 1.05 (6H, d, J=5.1 Hz)
Example 76
Using 0.2 g of
{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-yl}methylamine
obtained in Reference Example 25, 0.24 g of white powdery
N-{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-ylmethyl}-3-meth-
oxypicolinamide was obtained in the same manner as in Example
1.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.24-8.19 (2H, m), 7.72 (1H, dd,
J=8.4, 1.8 Hz), 7.65 (1H, d, J=0.9 Hz), 7.62 (1H, d, J=1.8 Hz),
7.43-7.35 (2H, m), 6.98 (1H, d, J=8.4 Hz), 4.60 (2H, dd, J=5.7, 0.9
Hz), 4.46 (2H, q, J=5.4 Hz), 3.95 (3H, s), 3.93 (3H, s)
Using 0.2 g of
{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-yl}methylamine
obtained in Reference Example 25, compounds of Example 77 to 79
were obtained in the same manner as in Example 1.
Example 77
N-{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-ylmethyl}-3-ethox-
ypicolinamide
Yield 0.24 g
White Powder
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.26-8.22 (2H, m), 7.72 (1H, dd,
J=8.4, 2.1 Hz), 7.65 (1H, s), 7.63 (1H, d, J=1.8 Hz), 7.40-7.32
(2H, m), 6.98 (1H, d, J=8.1 Hz), 4.62 (2H, dd, J=5.7, 0.9 Hz), 4.46
(2H, q, J=8.4 Hz), 4.18 (2H, q, J=6.9 Hz), 1.52 (3H, t, J=6.9
Hz)
Example 78
N-{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-ylmethyl}-2-metho-
xybenzamide
Yield 0.18 g
White Powder
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.42 (1H, br s), 8.23 (1H, dd,
J=7.5, 1.8 Hz), 7.73 (1H, dd, J=8.4, 2.1 Hz), 7.65-7.60 (2H, m),
7.48-7.42 (1H, m), 7.08 (1H, td, J=8.4, 0.9 Hz), 6.98 (1H, d, J=8.4
Hz), 4.62 (2H, dd, J=5.4, 0.9 Hz), 4.46 (2H, q, J=8.4 Hz), 3.98
(3H, s), 3.93 (3H, s)
Example 79
N-{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-ylmethyl}-2-methy-
lbenzamide
Yield 0.15 g
White Powder
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.72 (1H, dd, J=8.4, 2.1 Hz),
7.66 (1H, s), 7.61 (1H, d, J=2.1 Hz), 7.41-7.14 (4H, m), 6.98 (1H,
d, J=8.4 Hz), 6.31 (1H, br s), 4.58 (2H, dd, J=5.4, 0.9 Hz), 4.45
(2H, q, J=8.4 Hz), 3.93 (3H, s), 2.46 (3H, s)
Using 0.15 g of
{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-yl}methylamine
obtained Reference Example 25, compounds of Examples 80 to 82 were
obtained in the same manner as in Example 1.
Example 80
N-{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-ylmethyl}-2-propo-
xybenzamide
Yield 0.15 g
White Powder
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.53 (1H, br s), 8.24 (1H, dd,
J=7.8, 1.8 Hz), 7.73 (1H, dd, J=8.4, 2.1 Hz), 7.65-7.60 (2H, m),
7.45-7.38 (1H, m), 7.09-6.93 (3H, m), 4.62 (2H, d, J=5.1 Hz), 4.45
(2H, q, J=8.1 Hz), 4.07 (2H, t, J=6.6 Hz), 3.94 (3H, s), 1.88 (2H,
qt, J=7.5, 6.6 Hz), 0.98 (3H, t, J=7.5 Hz)
Example 81
N-{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-ylmethyl}-2-isopr-
opoxybenzamide
Yield 0.18 g
White Powder
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.64 (1H, br s), 8.23 (1H, dd,
J=7.8, 1.8 Hz), 7.74 (1H, dd, J=8.4, 2.1 Hz), 7.65 (1H, d, J=2.1
Hz), 7.63 (1H, s), 7.44-7.37 (1H, m), 7.08-6.94 (3H, m), 4.73 (1H,
tt, J=6.0 Hz), 4.62 (2H, dd, J=5.1, 0.9 Hz), 4.46 (2H, q, J=8.4
Hz), 3.94 (3H, s), 1.41 (6H, d, J=6.0 Hz)
Example 82
N-{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-ylmethyl}-4-chlor-
o-2-methoxybenzamide
Yield 0.21 g
White Powder
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.29 (1H, br s), 8.17 (1H, d,
J=8.4 Hz), 7.73 (1H, dd, J=8.4, 1.8 Hz), 7.64 (1H, d, J=1.5 Hz),
7.07 (1H, dd, J=8.4, 1.8 Hz), 7.00-6.96 (2H, m), 4.60 (2H, dd,
J=5.4, 0.9 Hz), 4.46 (2H, q, J=8.4 Hz), 3.98 (3H, s), 3.93 (3H,
s)
Example 83
Using 0.1 g of
{2-[3-cyclopropylmethoxy-4-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-yl}meth-
ylamine obtained in Reference Example 34, 0.11 g of white powdery
N-{2-[3-cyclopropylmethoxy-4-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-ylmet-
hyl}-2-ethoxybenzamide was obtained in the same manner as in
Example 1.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.54 (1H, br s), 8.23 (1H, dd,
J=7.8, 1.8 Hz) 7.64 (1H, s), 7.60-7.55 (2H, m), 7.45-7.38 (1H, m),
7.10-7.04 (2H, m), 6.94 (1H, d, J=8.1 Hz), 4.62 (2H, dd, J=5.4, 0.9
Hz), 4.48 (2H, q, J=8.4 Hz), 4.18 (2H, q, J=6.9 Hz), 3.95 (2H, d,
J=7.2 Hz), 1.48 (3H, t, J=7.2 Hz), 1.35-1.29 (1H, m), 0.70-0.63
(2H, m), 0.41-0.35 (2H, m)
Example 84
Using 0.18 g of
{2-[3-cyclopropylmethoxy-4-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-yl}meth-
ylamine obtained in Reference Example 34, 0.2 g of white powdery
N-{2-[3-cyclopropylmethoxy-4-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-ylmet-
hyl}-3-methylpicolinamide was obtained in the same manner as in
Example 1.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.57 (1H, br s), 8.39 (1H, dd,
J=4.5, 1.2 Hz) 7.64 (1H, s), 7.60-7.55 (3H, m), 7.32-7.26 (1H, m),
7.06-7.03 (1H, m), 4.59 (2H, dd, J=5.7, 0.9 Hz), 4.48 (2H, q, J=8.4
Hz), 3.95 (2H, d, J=6.9 Hz), 2.76 (3H, s), 1.38-1.28 (1H, m),
0.69-0.62 (2H, m), 0.40-0.35 (2H, m)
Example 85
Using 0.3 g of [2-(3,4-diethoxyphenyl)oxazol-4-yl]methylamine
obtained in Reference Example 37, 0.11 g of white powdery
N-[2-(3,4-diethoxyphenyl)oxazol-4-ylmethyl]-2-propoxy benzamide was
obtained in the same manner as in Example 1.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.51 (1H, br s), 8.24 (1H, dd,
J=7.8, 1.8 Hz), 7.60-7.50 (3H, m), 7.41 (1H, m), 7.06 (1H, m),
7.00-6.90 (2H, m), 4.61 (2H, d, J=5.1 Hz), 4.06 (2H, t, J=6.6 Hz),
1.87 (2H, tq, J=7.2, 6.6 Hz), 1.49 (6H, t, J=6.9 Hz), 0.96 (3H, t,
J=7.2 Hz)
Using 0.3 g of [2-(3,4-diethoxyphenyl)oxazol-4-yl]methylamine
obtained in Reference Example 37, compounds of Examples 86 to 91
were obtained in the same manner as in Example 1.
Example 86
N-[2-(3,4-diethoxyphenyl)oxazol-4-ylmethyl]-2-trifluoromethyl
benzamide
Yield 0.11 g
White Powder
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.75-7.50 (7H, m), 6.91 (1H, d,
J=8.4 Hz), 6.32 (1H, br s), 4.59 (2H, d, J=5.4 Hz), 4.17 (2H, q,
J=6.9 Hz), 4.14 (2H, q, J=6.9 Hz), 1.48 (6H, t, J=6.9 Hz)
Example 87
N-[2-(3,4-diethoxyphenyl)oxazol-4-ylmethyl]picolinamide
Yield 0.34 g
White Powder
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.55 (1H, m), 8.47 (1H, br s),
8.21 (1H, d, J=7.8 Hz), 7.85 (1H, m), 7.57 (1H, dd, J=8.4, 1.8 Hz),
7.55 (1H, d, J=1.8 Hz), 7.42 (1H, m), 6.91 (1H, d, J=8.4 Hz), 6.32
(1H, br s), 4.63 (2H, d, J=6.0 Hz), 4.18 (2H, q, J=6.9 Hz), 4.15
(2H, q, J=6.9 Hz), 1.48 (3H, t, J=6.9 Hz), 1.48 (3H, t, J=6.9
Hz)
Example 88
N-[2-(3,4-diethoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide
Yield 0.23 g
White Powder
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.55 (1H, m), 8.47 (1H, br s),
8.21 (1H, d, J=7.8 Hz), 7.85 (1H, m), 7.57 (1H, dd, J=8.4, 1.8 Hz),
7.55 (1H, d, J=1.8 Hz), 7.42 (1H, m), 6.91 (1H, d, J=8.4 Hz), 6.32
(1H, br s), 4.63 (2H, d, J=6.0 Hz), 4.18 (2H, q, J=6.9 Hz), 4.15
(2H, q, J=6.9 Hz), 1.48 (3H, t, J=6.9 Hz), 1.48 (3H, t, J=6.9
Hz)
Example 89
N-[2-(3,4-diethoxyphenyl)oxazol-4-ylmethyl]-4-ethoxybenzamide
Yield 0.32 g
White Powder
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.80-7.70 (2H, m), 7.63 (1H, s),
7.60-7.50 (2H, m), 6.95-6.85 (3H, m), 6.66 (1H, br s), 4.57 (2H, q,
J=6.0 Hz), 4.17 (2H, q, J=6.9 Hz), 4.15 (2H, q, J=6.9 Hz), 4.06
(2H, q, J=6.9 Hz), 1.48 (3H, t, J=6.9 Hz), 1.48 (3H, t, J=6.9 Hz),
1.42 (3H, t, J=6.9 Hz).
Example 90
N-[2-(3,4-diethoxyphenyl)oxazol-4-ylmethyl]-5-methoxy-2-trifluoro
methoxybenzamide
Yield 0.34 g
White Powder
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.95 (1H, br s), 7.73 (1H, d,
J=3.0 Hz), 7.70-7.50 (3H, m), 6.99 (1H, dd, J=9.0, 3.0 Hz),
6.90-6.80 (2H, m), 4.61 (2H, d, J=6.0 Hz), 4.18 (2H, q, J=6.9 Hz),
4.15 (2H, q, J=6.9 Hz), 3.82 (3H, s), 1.48 (3H, t, J=6.9 Hz), 1.46
(3H, t, J=6.9 Hz)
Example 91
N-[2-(3,4-diethoxyphenyl)oxazol-4-ylmethyl]-3-ethoxybenzamide
Yield 0.12 g
White Powder
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.57 (1H, dd, J=8.1, 2.1 Hz),
7.53 (1H, d, J=2.1 Hz), 7.35-7.25 (3H, m), 7.01 (1H, m), 6.92 (1H,
d, J=8.1 Hz), 6.68 (1H, br s), 4.58 (2H, d, J=5.4 Hz), 4.18 (2H, q,
J=6.9 Hz), 4.15 (2H, q, J=6.9 Hz), 4.07 (2H, q, J=6.9 Hz), 1.49
(3H, t, J=6.9 Hz), 1.48 (3H, t, J=6.9 Hz), 1.42 (3H, t, J=6.9
Hz)
Example 92
Using 0.3 g of [2-(3,4-dimethoxyphenyl)oxazol-4-yl]methylamine
obtained in Reference Example 40, 0.27 g of white powdery
N-[2-(3,4-dimethoxyphenyl)oxazol-4-ylmethyl]-2-ethoxy benzamide was
obtained in the same manner as in Example 1.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.56 (1H, br s), 8.24 (1H, dd,
J=8.1, 1.8 Hz), 7.65-7.60 (2H, m), 7.55 (1H, d, J=1.5 Hz), 7.42
(1H, m), 7.07 (1H, m), 6.95-6.90 (2H, m), 4.63 (2H, d, J=5.1 Hz),
4.18 (2H, q, J=6.9 Hz), 3.98 (3H, s), 3.97 (3H, s), 1.26 (3H, t,
J=6.9 Hz)
Example 93
Using 0.25 g of [2-(3,4-dimethoxyphenyl)oxazol-4-yl]methylamine
obtained in Reference Example 40, 0.23 g of white powdery
N-[2-(3,4-dimethoxyphenyl)oxazol-4-ylmethyl]-2-ethyl benzamide was
obtained in the same manner as in Example 1.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.66 (1H, s), 7.60 (1H, dd,
J=8.4, 1.8 Hz), 7.52 (1H, d, J=1.8 Hz), 7.40-7.20 (4H, m), 6.93
(1H, d, J=8.4 Hz), 6.34 (1H, br s), 4.58 (2H, d, J=5.4 Hz), 3.96
(3H, s), 3.94 (3H, s), 2.82 (2H, q, J=7.5 Hz), 1.20 (3H, t, J=7.5
Hz)
Example 94
Using 0.2 g of [2-(3,4-dimethoxyphenyl)oxazol-4-yl]methylamine
obtained in Reference Example 40, 0.16 g of white powdery
N-[2-(3,4-dimethoxyphenyl)oxazol-4-ylmethyl]-3-methyl picolinamide
was obtained in the same manner as in Example 1.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.58 (1H, br s), 8.39 (1H, m),
7.65-7.55 (4H, m), 7.30 (1H, m), 6.92 (1H, d, J=8.4 Hz), 4.59 (2H,
d, J=6.0 Hz), 3.97 (3H, s), 3.93 (3H, s), 2.76 (3H, s), 1.58 (3H,
s)
Example 95
Using 0.2 g of [2-(3,4-dimethoxyphenyl)oxazol-4-yl]methylamine
obtained in Reference Example 40, 0.12 g of white powdery
N-[2-(3,4-dimethoxyphenyl)oxazol-4-ylmethyl]-3-methoxy picolinamide
was obtained in the same manner as in Example 1.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.21 (1H, br s), 8.20 (1H, dd,
J=3.9, 1.8 Hz), 7.65 (1H, s), 7.61 (1H, dd, J=8.4, 1.8 Hz), 7.54
(1H, d, J=1.8 Hz), 7.45-7.30 (2H, m), 6.92 (1H, d, J=8.4 Hz), 4.61
(2H, d, J=6.0 Hz), 3.97 (3H, s), 3.96 (3H, s), 3.93 (3H, s)
Example 96
0.13 g of
[2-(3-benzyloxy-4-difluoromethoxyphenyl)oxazol-4-yl]methylamine
obtained in Reference Example 46 was suspended in 10 ml of acetone.
Then 0.14 g of 1-hydroxybenzotriazole and 0.19 g of
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and
0.14 g of 3-methyl picolinate were added to the obtained suspension
and the mixture was refluxed for 30 minutes. The reaction mixture
was concentrated under reduced pressure, and water was added to the
residue. Ethyl acetate extraction was performed. The organic layer
was washed twice with water, and concentrated. The residue was
purified by silica gel column chromatography (n-hexane:ethyl
acetate=1:1), yielding 0.16 g of white powdery
N-[2-(3-benzyloxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-3-me-
thylpicolinamide.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.56 (1H, br s), 8.40 (1H, d,
J=3.9 Hz), 7.74-7.58 (4H, m), 7.47-7.23 (7H, m), 6.62 (1H, t,
J=74.7 Hz), 5.21 (2H, s), 4.60 (2H, d, J=5.7 Hz), 2.76 (3H, s)
Example 97
0.16 g of
N-[2-(3-benzyloxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-3--
methylpicolinamide obtained in Example 96 was dissolved in 5 ml of
ethanol, 20 mg of 10% palladium carbon powder was added thereto,
and the mixture was stirred at room temperature for 30 minutes
under a hydrogen atmosphere. The catalyst was filtered off, and the
filtrate was concentrated to obtain 0.12 g of white powdery
N-[2-(4-difluoromethoxy-3-hydroxyphenyl)oxazol-4-ylmethyl]-3-methylpicoli-
namide.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.60-8.54 (1H, m), 8.39 (1H, d,
J=3.3 Hz), 7.69-7.55 (4H, m), 7.37-7.28 (1H, m), 7.18 (1H, d, J=8.4
Hz), 6.59 (1H, t, J=73.2 Hz), 5.79 (1H, br s), 4.59 (2H, dd, J=6.0,
0.9 Hz), 2.76 (3H, s)
Example 98
0.12 g of
N-[2-(4-difluoromethoxy-3-hydroxyphenyl)oxazol-4-ylmethyl]-3-me-
thylpicolinamide obtained in Example 97 and 0.15 ml of
1,8-diazabicyclo[5,4,0]undec-7-ene were dissolved in 4 ml of
ethanol. 0.15 ml of (bromomethyl)cyclopropane was added thereto and
refluxed with heating for 3 hours. The solvent was distilled off,
and water was added to the residue. Ethyl acetate extraction was
performed. The organic layer was washed twice with water, and
concentrated. The residue was purified by silica gel column
choromatography (n-hexane:ethyl acetate=1:1). The obtained crude
crystals were recrystallized using an ethanol-n-hexane mixture, and
60 mg of white powdery
N-[2-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-3-m-
ethylpicolinamide was obtained.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.59-8.54 (1H, m), 8.39 (1H, dd,
J=4.5, 1.2 Hz), 7.67 (1H, s), 7.63-7.56 (3H, m), 7.37-7.28 (1H, m),
7.22 (1H, d, J=8.1 Hz), 6.69 (1H, t, J=75.0 Hz), 4.59 (2H, dd,
J=5.7, 0.9 Hz), 3.98 (2H, d, J=6.9 Hz), 2.76 (3H, s), 1.35-1.20
(1H, m), 0.70-0.63 (2H, m), 0.41-0.35 (2H, m)
Example 99
Using 0.2 g of
[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-yl]methylamine
obtained in Reference Example 13, 0.11 g of white powdery
N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]isoquinoline-
-1-carboxamide was obtained in the same manner as in Example 1.
.sup.1H-NMR (CDCl.sub.3) .delta.: 9.60 (1H, m), 8.67 (1H, br s),
8.47 (1H, d, J=2.4 Hz), 7.90-7.80 (2H, m), 7.75-7.65 (3H, m), 7.61
(1H, dd, J=8.4, 1.8 Hz), 7.53 (1H, d, J=1.8 Hz), 6.92 (1H, d, J=8.4
Hz), 4.68 (2H, d, J=6.0 Hz), 3.94 (2H, d, J=7.5 Hz), 3.92 (3H, s),
1.39 (1H, m), 0.70-0.60 (2H, m), 0.40-0.35 (2H, m)
Example 100
4.42 g of sodium hydroxide was suspended in 160 ml of
dimethoxyethane. The suspension was stirred with ice cooling while
16 g of 3-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-yl]methyl
propionate obtained in Reference Example 48 and 39.23 g of
2-ethoxyperbenzoic acid were separately added, and then heating and
refluxing were conducted for 7 hours. After cooling with ice,
saturated ammonium chloride solution was added to the mixture and
stirred for 30 minutes. Water was then added thereto, and ethyl
acetate extraction was performed, followed by drying over anhydrous
magnesium sulfate, and the solvent was then distilled off. The
residue was subjected to silica gel column purification
(n-hexane:ethyl acetate=3:1), and 13.4 g of yellow oily substance,
methyl
2-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-(2-ethoxyphenyl)-3-
-oxopropionate was obtained.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.71 (1H, d, J=7.8 Hz), 7.57-7.54
(3H, m), 7.48-7.28 (6H, m), 6.99-6.90 (3H, m), 5.16 (2H, s), 4.98
(1H, t, J=6.9 Hz), 4.14 (2H, q, J=6.9 Hz), 3.91 (3H, s), 3.70 (3H,
s), 3.27-3.19 (2H, m), 1.45 (3H, t, J=6.9 Hz)
Example 101
A 13.4 g quantity of methyl
2-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-(2-ethoxyphenyl)-3-
-oxopropionate obtained in Example 100 was suspended in 67 ml of
ethanol, 67 ml of 47% hydrobromic acid was added thereto, and the
suspension was heated and refluxed overnight. After standing to
cool, the crystals generated were collected by filtration, washed
with water and diisopropyl ether, and dried, thereby yielding 8.1 g
of white powdery
1-(2-ethoxyphenyl)-3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]propan-1-o-
ne.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.30 (1H, d, J=8.7 Hz), 7.84 (1H,
d, J=1.8 Hz), 7.83-7.71 (2H, m), 7.45 (1H, t, J=8.4 Hz), 7.06 (1H,
d, J=8.7 Hz), 6.99-6.93 (2H, m), 4.17 (2H, q, J=6.9 Hz), 4.00 (3H,
s), 3.67 (2H, t, J=6.6 Hz), 3.35 (2H, t, J=6.6 Hz), 1.55 (3H, t,
J=6.9 Hz)
Example 102
A 8.1 g quantity of
1-(2-ethoxyphenyl)-3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]propan-1-o-
ne obtained in Example 101 was suspended in 220 ml of ethanol, 10 g
of 1,8-diazabicyclo[5,4,0]undec-7-ene and 5.96 g of
(bromomethyl)cyclopropane were added thereto, and stirring was
conducted for 5 hours while heating and refluxing. After distilling
off ethanol under reduced pressure, water was added, ethyl acetate
extraction was performed, followed by drying over anhydrous
magnesium sulfate and distilling the solvent off. The residue was
subjected to silica gel column purification (n-hexane:ethyl
acetate=4:1), and the obtained crude crystals were recrystallized
using ethanol, thereby yielding 4.4 g of white powdery
3-[2-(3-cycropropylmethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-ethoxy
phenyl)propan-1-one.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.70 (1H, dd, J=7.5, 1.8 Hz),
7.56 (1H, dd, J=8.4, 2.1 Hz), 7.50 (1H, s), 7.45-7.39 (2H, m),
7.00-6.89 (3H, m), 4.13 (2H, q, J=7.2 Hz), 3.93-3.91 (5H, m), 3.41
(2H, t, J=6.6 Hz), 2.99 (2H, t, J=6.6 Hz), 1.51 (3H, t, J=7.2 Hz),
1.47 (1H, m), 0.67-0.64 (2H, m), 0.40-0.36 (2H, m)
Example 103
A 0.3 g quantity of
1-(2-ethoxyphenyl)-3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]propan-1-o-
ne obtained in Example 101 was suspended in 10 ml of ethanol, 0.37
g of 1,8-diazabicyclo[5,4,0]undec-7-ene and 0.26 g of ethyl iodide
were added thereto, and the suspension was stirred for 4 hours
while heating and refluxing. After distilling off ethanol under
reduced pressure, water was added, ethyl acetate extraction was
performed, followed by drying over anhydrous magnesium sulfate and
distilling the solvent off. The residue was subjected to silica gel
column purification (n-hexane:ethyl acetate=3:1), thereby yielding
0.15 g of white powdery
3-[2-(3-ethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-on-
e.
.sup.1H -NMR (CDCl.sub.3) .delta.: 7.70 (1H, dd, J=7.5, 1.8 Hz),
7.56 (1H, dd, J=8.4, 1.8 Hz), 7.52-7.40 (2H, m), 6.99-6.89 (3H, m),
4.21-4.09 (4H, m), 3.91 (3H, s), 3.42 (2H, t, J=6.9 Hz), 2.99 (2H,
t, J=6.9 Hz), 1.51-1.45 (6H, m)
Example 104
A 0.3 g quantity of
1-(2-ethoxyphenyl)-3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]propan-1-o-
ne obtained in Example 101 was suspended in 10 ml of ethanol, 0.37
g of 1,8-diazabicyclo[5,4,0]undec-7-ene and 0.14 ml of allyl
bromide were added thereto, and stirring was conducted for 3 hours
while heating and refluxing. After distilling off ethanol under
reduced pressure, water was added, ethyl acetate extraction was
performed, followed by drying over anhydrous magnesium sulfate and
distilling the solvent off. The residue was subjected to silica gel
column purification (n-hexane:ethyl acetate=3:1), thereby yielding
0.2 g of white powdery
3-[2-(3-allyloxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1--
one.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.70 (1H, dd, J=7.8, 1.8 Hz),
7.58 (1H, dd, J=8.4, 1.8 Hz), 7.52 (1H, d, J=1.8 Hz), 7.45-7.40
(2H, m), 7.00-6.90 (3H, m), 6.18-6.05 (1H, m), 5.47-5.29 (2H, m),
4.67 (2H, d, J=5.1 Hz), 4.13 (2H, q, J=6.9 Hz), 3.92 (3H, s), 3.42
(2H, t, J=7.2 Hz), 2.99 (2H, t, J=7.2 Hz), 1.47 (3H, t, J=6.9
Hz).
Using 1-(2-ethoxyphenyl)-3-[2-(3-hydroxy-4-methoxy
phenyl)oxazol-4-yl]propan-1-one obtained in Example 101, compounds
of Examples 105 to 110 were obtained in the same manner as in
Examples 102.
Example 105
3-[2-(3-cyclopentyloxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)prop-
an-1-one
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.70 (1H, dd, J=7.5, 1.8 Hz),
7.57-7.51 (2H, m), 7.45-7.39 (2H, m), 6.99-6.88 (3H, m), 4.88 (1H,
br s), 4.12 (2H, q, J=6.9 Hz), 3.88 (3H, s), 3.42 (2H, t, J=6.9
Hz), 2.99 (2H, t, J=6.9 Hz), 2.04-1.87 (6H, m), 1.65-1.60 (2H, m),
1.47 (3H, t, J=6.9 Hz)
Example 106
3-[2-(3-isobutoxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1--
one
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.70 (1H, dd, J=7.5, 1.8 Hz),
7.55 (1H, dd, J=8.4, 1.8 Hz), 7.50 (1H, d, J=2.1 Hz), 7.45-7.40
(2H, m), 4.13 (2H, q, J=6.9 Hz), 3.90 (3H, s), 3.84 (2H, d, J=6.9
Hz), 3.42 (2H, t, J=7.2 Hz), 3.00 (2H, t, J=7.2 Hz), 2.23-2.14 (1H,
m), 1.48 (3H, t, J=6.9 Hz), 1.05 (6H, d, J=6.9 Hz)
Example 107
1-(2-ethoxyphenyl)-3-[2-(4-methoxy-3-propoxyphenyl)oxazol-4-yl]propan-1-on-
e
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.70 (1H, dd, J=7.5, 1.8 Hz),
7.56 (1H, dd, J=8.1, 1.8 Hz), 7.52 (1H, s), 7.45-7.40 (2H, m),
7.00-6.89 (3H, m), 4.13 (2H, q, J=6.9 Hz), 4.05 (2H, t, J=6.9 Hz),
3.90 (3H, s), 3.42 (2H, t, J=7.5 Hz), 3.00 (2H, t, J=7.5 Hz),
1.95-1.84 (2H, m), 1.47 (3H, t, J=6.9 Hz), 1.05 (3H, t, J=6.9
Hz)
Example 108
3-[2-(3-(3-butenyloxy)-4-methoxyphenyl)oxazol-4-yl]-1-(2-ethoxy
phenyl)propan-1-one
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.70 (1H, dd, J=7.5, 1.8 Hz),
7.57 (1H, dd, J=8.4, 1.8 Hz), 7.52 (1H, s), 7.45-7.40 (2H, m),
6.97-6.89 (3H, m), 6.00-5.90 (1H, m), 5.22-5.10 (2H, m), 4.17-4.11
(4H, m), 3.90 (3H, s), 3.42 (2H, t, J=7.5 Hz), 3.00 (2H, t, J=7.5
Hz), 2.67-2.62 (2H, m), 1.47 (3H, t, J=6.9 Hz)
Example 109
3-[2-(3-butoxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-one
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.70 (1H, dd, J=7.5, 1.8 Hz),
7.57 (1H, dd, J=8.4, 1.8 Hz), 7.53 (1H, d, J=2.1 Hz), 7.45-7.39
(2H, m), 7.00-6.89 (3H, m), 4.16-4.07 (4H, m), 3.98 (3H, s), 3.42
(2H, t, J=7.2 Hz), 3.00 (2H, t, J=7.2 Hz), 1.90-1.86 (2H, m),
1.57-1.42 (5H, m), 0.99 (3H, t, J=7.2 Hz)
Example 110
1-(2-ethoxyphenyl)-3-[2-(4-methoxy-3-(2-propenyloxy)phenyl)oxazol-4-yl]pro-
pan-1-one
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.70 (1H, dd, J=7.8, 1.8 Hz),
7.66-7.63 (2H, m), 7.46-7.39 (2H, m), 7.00-6.92 (3H, m), 4.83 (2H,
d, J=2.1 Hz), 4.13 (2H, q, J=6.9 Hz), 3.92 (3H, s), 3.42 (2H, t,
J=7.2 Hz), 2.99 (2H, t, J=7.2 Hz), 2.52 (1H, t, J=2.1 Hz), 1.47
(3H, t, J=6.9 Hz)
Example 111
A 5.0 g quantity of
1-(2-ethoxyphenyl)-3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]propan-1-o-
ne obtained in Example 101 was dissolved in 50 ml of
dimethylformamide, 3.35 g of 2-bromopropane and 5.63 g of potassium
carbonate were added thereto, and stirring was conducted overnight
at room temperature. Water was added to the obtained mixture, ethyl
acetate extraction was performed, followed by drying over anhydrous
magnesium sulfate and distilling the solvent off. The residue was
subjected to silica gel column purification (n-hexane:ethyl
acetate=4:1), and the obtained crude crystals were recrystallized
using ethanol, thereby yielding 2.99 g of white powdery
1-(2-ethoxyphenyl)-3-[2-(3-isopropoxy-4-methoxyphenyl)oxazol-4-yl]propan--
1-one.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.70 (1H, dd, J=7.5, 1.8 Hz),
7.59-7.54 (2H, m), 7.45-7.39 (2H, m), 7.00-6.89 (3H, m), 4.68-4.60
(1H, m), 4.13 (2H, q, J=6.9 Hz), 3.89 (3H, s), 3.42 (2H, t, J=7.5
Hz), 2.99 (2H, t, J=7.5 Hz), 1.47 (3H, t, J=6.9 Hz), 1.39 (6H, d,
J=6.3 Hz)
Using 1-(2-ethoxyphenyl)-3-[2-(3-hydroxy-4-methoxy
phenyl)oxazol-4-yl]propane-1-one obtained in Example 101, compounds
of Examples 112 to 122 were obtained in the same manner as in
Example 111.
Example 112
1-(2-ethoxyphenyl)-3-{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol--
4-yl}propan-1-one
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.72-7.68 (2H, m), 7.60 (1H, d,
J=1.8 Hz), 7.45-7.39 (2H, m), 7.00-6.92 (3H, m), 4.44 (2H, q, J=8.4
Hz), 4.13 (2H, q, J=6.6 Hz), 3.90 (3H, s), 3.42 (2H, t, J=6.9 Hz),
2.99 (2H, t, J=6.9 Hz), 1.48 (3H, t, J=6.6 Hz)
Example 113
3-[2-(3-cyclohexylmethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)p-
ropan-1-one
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.70 (1H, dd, J=7.5, 1.8 Hz),
7.55 (1H, dd, J=8.4, 1.8 Hz), 7.50 (1H, d, J=1.8 Hz), 7.45-7.40
(2H, m), 7.00-6.88 (3H, m), 4.14 (2H, q, J=6.9 Hz), 3.90 (3H, s),
3.86 (2H, d, J=6.0 Hz), 3.42 (2H, t, J=7.2 Hz), 2.99 (2H, t, J=7.2
Hz), 2.00-1.86 (3H, m), 1.79-1.63 (3H, m), 1.45 (3H, t, J=6.9 Hz),
1.40-1.22 (2H, m), 1.10-1.02 (2H, m)
Example 114
3-[2-(3-cyclopentylmethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)-
propan-1-one
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.70 (1H, dd, J=7.5, 1.8 Hz),
7.55 (1H, dd, J=8.4, 1.8 Hz), 7.50 (1H, d, J=1.8 Hz), 7.45-7.40
(2H, m), 7.00-6.88 (3H, m), 4.14 (2H, q, J=6.9 Hz), 3.95 (2H, d,
J=7.2 Hz), 3.90 (3H, s), 3.42 (2H, t, J=7.2 Hz), 3.00 (2H, t, J=7.2
Hz), 2.48-2.44 (1H, m), 2.04-1.86 (2H, m), 1.63-1.50 (4H, m), 1.45
(3H, s), 1.39-1.35 (2H, m)
Example 115
1-(2-ethoxyphenyl)-3-[2-(4-methoxy-3-(4-pentenyloxy)phenyl)
oxazol-4-yl]propan-1-one
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.70 (1H, dd, J=7.5, 2.1 Hz),
7.56 (1H, dd, J=8.1, 2.1 Hz), 7.51 (1H, d, J=2.1 Hz), 7.45-7.39
(2H, m), 7.00-6.89 (3H, m), 5.87-5.81 (1H, m), 5.10-4.99 (2H, m),
4.17-4.08 (4H, m), 3.91 (3H, s), 3.42 (2H, t, J=7.2 Hz), 2.99 (2H,
t, J=7.2 Hz), 2.27-2.22 (2H, m), 2.04-1.95 (2H, m), 1.47 (3H, t,
J=7.2 Hz)
Example 116
3-[2-(3-cyclobutylmethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)p-
ropan-1-one
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.70 (1H, dd, J=7.5, 2.1 Hz),
7.56 (1H, dd, J=8.1, 2.1 Hz), 7.51 (1H, d, J=2.1 Hz), 7.45-7.39
(2H, m), 7.00-6.80 (3H, m), 4.13 (2H, q, J=7.2 Hz), 4.07 (2H, d,
J=7.2 Hz), 3.90 (3H, s), 3.42 (2H, t, J=7.2 Hz), 3.00 (2H, t, J=7.2
Hz), 2.96-2.85 (1H, m), 2.20-2.14 (2H, m), 1.91-1.80 (2H, m), 1.45
(3H, t, J=7.2 Hz)
Example 117
1-(2-ethoxyphenyl)-3-{2-[4-methoxy-3-(3-methyl-2-butenyloxy)phenyl]oxazol--
4-yl}propan-1-one
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.70 (1H, dd, J=7.5, 1.8 Hz),
7.57 (1H, dd, J=8.1, 1.8 Hz), 7.51 (1H, d, J=1.8 Hz), 7.00-6.89
(3H, m), 5.55 (1H, t, J=6.6 Hz), 4.64 (2H, d, J=6.6 Hz), 4.13 (2H,
q, J=6.9 Hz), 3.91 (3H, s), 3.42 (2H, t, J=7.2 Hz), 3.00 (2H, t,
J=7.2 Hz), 1.77 (6H, d, J=6.6 Hz), 1.45 (3H, t, J=6.9 Hz)
Example 118
3-{2-[3-(2-cyclohexenyloxy)-4-methoxyphenyl]oxazol-4-yl}-1-(2-ethoxyphenyl-
)propan-1-one
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.70 (1H, dd, J=7.5, 1.8 Hz),
7.60-7.57 (2H, m), 7.42-7.39 (2H, m), 7.00-6.89 (3H, m), 6.00-5.92
(2H, m), 4.88 (1H, br s), 4.15 (2H, q, J=7.2 Hz), 3.89 (3H, s),
3.42 (2H, t, J=7.2 Hz), 2.99 (2H, t, J=7.2 Hz), 2.04-1.80 (4H, m),
1.72-1.53 (2H, m), 1.45 (3H, t, J=7.2 Hz)
Example 119
1-(2-ethoxyphenyl)-3-[2-(4-methoxy-3-phenethyloxyphenyl)oxazol-4-yl]propan-
-1-one
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.69 (1H, dd, J=7.8, 1.8 Hz),
7.59 (1H, dd, J=8.4, 1.8 Hz), 7.56 (1H, d, J=1.8 Hz), 7.51-6.98
(7H, m), 6.95-6.90 (3H, m), 4.27 (2H, t, J=7.2 Hz), 4.11 (2H, q,
J=6.9 Hz), 3.91 (3H, s), 3.41 (2H, t, J=7.2 Hz), 3.20 (2H, t, J=7.2
Hz), 2.98 (2H, t, J=7.2 Hz), 1.54 (3H, t, J=6.9 Hz)
Example 120
1-(2-ethoxyphenyl)-3-{2-[4-methoxy-3-(3-phenylpropoxy)phenyl]oxazol-4-yl}p-
ropan-1-one
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.70 (1H, dd, J=7.5, 1.8 Hz),
7.58 (1H, dd, J=8.4, 1.8 Hz), 7.56 (1H, d, J=1.8 Hz), 7.49-7.39
(2H, m), 7.30-7.15 (5H, m), 6.99-6.90 (3H, m), 4.16-4.08 (4H, m),
3.92 (3H, s), 3.42 (2H, t, J=7.2 Hz), 2.98 (2H, t, J=7.2 Hz), 2.84
(2H, t, J=8.1 Hz), 2.24-2.15 (2H, m), 1.46 (3H, t, J=6.9 Hz)
Example 121
3-{2-[3-(2-cyclopropylethoxy)-4-methoxyphenyl]oxazol-4-yl}-1-(2-ethoxyphen-
yl)propan-1-one
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.70 (1H, dd, J=7.8, 1.8 Hz),
7.57-7.55 (2H, m), 7.43-7.39 (2H, m), 7.00-6.89 (3H, m), 4.19-4.10
(4H, m), 3.91 (3H, s), 3.42 (2H, t, J=6.9 Hz), 3.01 (2H, t, J=6.9
Hz), 1.81-1.74 (2H, m), 1.48 (3H, t, J=6.9 Hz), 0.88-0.83 (1H, m),
0.52-0.47 (2H, m), 0.16-0.12 (2H, m)
Example 122
3-{2-[3-(2-cyclopentylethoxy)-4-methoxyphenyl]oxazol-4-yl}-1-(2-ethoxyphen-
yl)propan-1-one
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.70 (1H, dd, J=7.8, 1.8 Hz),
7.56 (1H, dd, J=8.4, 1.8 Hz), 7.51 (1H, d, J=2.1 Hz), 7.45-7.39
(2H, m), 7.00-6.89 (3H, m), 4.17-4.07 (4H, m), 3.90 (3H, s), 3.42
(2H, t, J=6.9 Hz), 3.00 (2H, t, J=6.9 Hz), 2.00-1.81 (5H, m),
1.66-1.62 (4H, m), 1.45 (3H, t, J=6.9 Hz), 1.28-1.15 (2H, m)
Example 123
A 1.0 g quantity of methyl
3-{2-[3-cyclopropylmethoxy-4-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-yl}pr-
opionate obtained in Reference Example 49 and 0.54 g of methyl
3-methoxypicolinate were added to 5 ml of dimethylformamide, and
the mixture was stirred with ice cooling for 10 minutes. A 0.83 g
of sodium t-pentoxide was added to the obtained mixture, which was
then stirred with ice cooling for an hour, followed by further
stirring at room temperature for 1 hour. The reaction mixture was
stirred with ice cooling, saturated ammonium chloride solution was
added thereto, and further stirred for 30 minutes. Water was added
to the mixture, ethyl acetate extraction was performed, followed by
drying over anhydrous magnesium sulfate and distilling the solvent
off. A 5.0 ml quantity of dimethylsulfoxide, 84 mg of lithium
chloride and 41 .mu.l of purified water were added to the residue,
and the mixture was stirred with heating at 110.degree. C.
overnight. After standing to cool, water was added to the obtained
mixture, ethyl acetate extraction was performed, followed by drying
over anhydrous magnesium sulfate and distilling the solvent off.
The obtained residue was subjected to silica gel column
purification (n-hexane:ethyl acetate=4:1), and the obtained crude
crystals were recrystallized from a mixture of ethyl acetate and
diisopropyl ether, thereby yielding 0.11 g white powdery
3-{2-[3-cyclopropyl
methoxy-4-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-yl}-1-(3-methoxy
pyridin-2-yl)propan-1-one.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.24 (1H, d, J=4.2 Hz), 7.55-7.47
(2H, m), 7.43 (1H, s), 7.40-7.35 (2H, m), 7.03 (1H, d, J=8.4 Hz),
4.46 (2H, q, J=7.2 Hz), 3.94 (2H, d, J=6.6 Hz), 3.90 (3H, s), 3.51
(2H, d, J=7.2 Hz), 3.01 (2H, d, J=7.2 Hz), 1.31-1.26 (1H, m),
0.68-0.62 (2H, m), 0.39-0.34 (2H, m)
Example 124
A 2 g quantity of methyl 3-[2-(3-benzyloxy-4-methoxy
phenyl)oxazol-4-yl]propionate obtained in Reference Example 48 and
1.1 g of methyl 3-methoxypicolinate were dissolved in 10 ml of
dimethylformamide, and while stirring the solution with ice cooling
1.81 g of sodium t-pentoxide was added thereto and stirred for 30
minutes. The mixture was further stirred for 5 hours at room
temperature, ice was added to the reaction mixture, followed by
addition of saturated aqueous ammonium chloride solution, and the
mixture was further stirred. After stirring the reaction mixture
for 30 minutes, water was added thereto and ethyl acetate
extraction was performed. The organic layer was washed twice with
water, and concentrated under reduced pressure. The obtained
residue was purified by silica gel column chromatography
(n-hexane:ethyl acetate=1:1), thereby yielding 1.55 g of white
amorphous methyl 2-[2-(3-benzyloxy-4-methoxy
phenyl)oxazol-4-ylmethyl]-3-(3-methoxypyridin-2-yl)-3-oxopropionate.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.24 (1H, dd, J=4.5, 1.8 Hz),
7.57-7.28 (10H, m), 6.91 (1H, d, J=9.0 Hz), 5.18-5.13 (3H, m),
3.91-3.90 (6H, m), 3.64 (3H, s), 3.36-3.18 (2H, m)
Example 125
A 1.5 g quantity of methyl
2-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-(3-methoxypyridin--
2-yl)-3-oxopropionate obtained in Example 124 was dissolved in 22.5
ml of ethanol, 7.5 ml of 47% hydrobromic acid was added thereto,
and the mixture was stirred with heating at 80.degree. C. for 7.5
hours. While stirring with ice cooling, the reaction mixture was
neutralized with a 5N sodium hydroxide solution, and ethyl acetate
extraction was performed. The organic layer was washed twice with
water, and concentrated under reduced pressure, and the obtained
residue was purified by silica gel column chromatography
(dichloromethane:methanol=20:1), thereby yielding 0.65 g of pale
yellow oily substance,
3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-3-(3-methoxypyridin-2-yl)pro-
pan-1-one.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.24 (1H, dd, J=7.2, 1.5 Hz),
7.55-7.27 (5H, m), 6.88 (1H, d, J=8.7 Hz), 5.72 (1H, s), 3.92-3.89
(6H, m), 3.51 (2H, t, J=7.5 Hz), 3.03 (2H, t, J=7.5 Hz)
Example 126
Using 0.24 g of
3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-3-(3-methoxypyridine-2-yl)pr-
opan-1-one obtained in Example 125, 0.11 g of white powdery
3-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-yl]-3-(3-methoxypyrid-
in-2-yl)propan-1-one was obtained in the same manner as in Example
102.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.24 (1H, dd, J=4.2, 1.2 Hz),
7.59-7.32 (5H, m), 6.91 (1H, d, J=8.4 Hz), 3.94-3.90 (8H, m), 3.51
(2H, t, J=7.2 Hz), 3.01 (2H, t, J=7.2 Hz), 1.40-1.30 (1H, m),
0.69-0.62 (2H, m), 0.41-0.35 (2H, m)
Using
3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-3-(3-methoxypyridin-2--
yl)propan-1-one obtained in Example 125, compounds of Examples 127
and 128 were obtained in the same manner as in Example 102.
Example 127
3-[2-(3-isobutoxy-4-methoxyphenyl)oxazol-4-yl]-3-(3-methoxy
pyridin-2-yl)propan-1-one
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.24 (1H, dd, J=4.2, 1.5 Hz),
7.58-7.30 (5H, m), 6.91 (1H, d, J=8.4 Hz), 3.92-3.90 (6H, m), 3.84
(2H, d, J=6.9 Hz), 3.52 (2H, t, J=7.2 Hz), 3.01 (2H, t, J=7.2 Hz),
2.20 (1H, q, J=6.9 Hz), 1.06 (6H, d, J=6.9 Hz)
Example 128
3-[2-(3-cyclopentyloxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methoxy
pyridin-2-yl)propan-1-one
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.24 (1H, dd, J=4.5, 1.5 Hz),
7.60-7.30 (5H, m), 6.90 (1H, d, J=8.7 Hz), 4.90-4.85 (1H, m),
3.90-3.88 (6H, m), 3.51 (2H, d, J=6.9 Hz), 3.01 (2H, t, J=6.9 Hz),
2.00-1.81 (6H, m), 1.64-1.60 (2H, m)
Example 129
Using 0.15 g of
3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-3-(3-methoxypyridin-2-yl)pro-
pan-1-one obtained in Example 125, 44 mg of white powdery
1-(3-methoxypyridin-2-yl)-3-{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl-
]oxazol-4-yl}propan-1-one was obtained in the same manner as in
Example 111.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.24 (1H, dd, J=4.2, 1.2 Hz),
7.70 (1H, dd, J=8.4, 1.8 Hz), 7.60 (1H, d, J=1.8 Hz), 7.51 (1H, d,
J=1.8 Hz), 7.47-7.32 (2H, m), 6.96 (1H, d, J=8.4 Hz), 4.45 (2H, q,
J=8.4 Hz), 3.95-3.88 (6H, m), 3.52 (2H, t, J=7.2 Hz), 3.01 (2H, t,
J=7.2 Hz)
Example 130
A 2 g quantity of methyl 3-[2-(3-benzyloxy-4-methoxy
phenyl)oxazol-4-yl]propionate obtained in Reference Example 48 and
1 g of methyl 3-ethoxypicolinate were dissolved in 10 ml of
dimethylformamide, and while stirring the solution with ice cooling
1.81 g of sodium t-pentoxide was added thereto and stirred for 30
minutes. The mixture was further stirred for 4 hours at room
temperature, and ice was added to the reaction mixture, followed by
addition of saturated aqueous ammonium chloride solution for
further stirring. After stirring the reaction mixture for 30
minutes, water was added thereto and ethyl acetate extraction was
performed. The organic layer was washed twice with water, and
concentrated under reduced pressure. The obtained residue was
purified by silica gel column chromatography (n-hexane:ethyl
acetate=1:1), thereby yielding 1.5 g of colorless oily substance
methyl
2-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-(3-ethoxypyridin-2-
-yl)-3-oxopropionate.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.22 (1H, dd, J=4.2, 1.2 Hz),
7.57-7.27 (10H, m), 6.91 (1H, d, J=9.0 Hz), 5.18-5.12 (3H, m), 4.12
(2H, q, J=6.9 Hz), 3.92 (3H, s), 3.65 (3H, s), 3.30-3.23 (2H, m),
1.46 (3H, t, J=6.9 Hz)
Example 131
Using 1.5 g of methyl
2-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-(3-ethoxypyridin-2-
-yl)-3-oxopropionate obtained in Example 130, 0.7 g of pale yellow
oily substance,
1-(3-ethoxypyridin-2-yl)-3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]prop-
an-1-one, was obtained in the same manner as in Example 125.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.23 (1H, dd, J=4.2, 1.2 Hz),
7.55-7.49 (2H, m), 7.45 (1H, s), 7.42-7.28 (2H, m), 6.88 (1H, d,
J=8.7 Hz), 5.70 (1H, s), 4.11 (2H, q, J=6.9 Hz), 3.49 (2H, t, J=7.2
Hz), 3.01 (2H, t, J=6.9 Hz), 1.46 (3H, t, J=6.9 Hz)
Example 132
Using 0.2 g of
1-(3-ethoxypyridin-2-yl)-3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]prop-
an-1-one obtained in Example 131, 0.2 g of pale yellow oily
substance,
3-[2-(3-cyclopentyloxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-ethoxypyridin-2--
yl)propan-1-one, was obtained in the same manner as in Example
102.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.23 (1H, dd, J=4.5, 1.5 Hz),
7.57-7.45 (2H, m), 7.44 (1H, d, J=0.9 Hz), 7.38-7.28 (2H, m), 6.89
(1H, d, J=8.7 Hz), 4.89-4.87 (1H, m), 4.12 (2H, q, J=6.9 Hz),
3.94-3.91 (5H, m), 3.88 (3H, s), 3.49 (2H, t, J=7.2 Hz), 3.01 (2H,
t, J=7.2 Hz), 2.01-1.81 (6H, m), 1.65-1.58 (2H, m), 1.47 (3H, t,
J=6.9 Hz)
Using 1-(3-ethoxypyridin-2-yl)-3-[2-(3-hydroxy-4-methoxy
phenyl)oxazol-4-yl]propan-1-one obtained in Example 131, compounds
of Examples 133 and 134 were obtained in the same manner as in
Example 102.
Example 133
3-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-ethoxypyridin-
-2-yl)propan-1-one
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.23 (1H, dd, J=4.2, 1.5 Hz),
7.57 (1H, dd, J=8.4, 1.8 Hz), 7.50 (1H, d, J=1.8 Hz), 7.45 (1H, d,
J=1.8 Hz), 7.38-7.28 (2H, m), 6.91 (1H, d, J=8.4 Hz), 4.12 (2H, q,
J=6.9 Hz), 3.94-3.91 (5H, m), 3.49 (2H, t, J=7.2 Hz), 3.02 (2H, t,
J=7.2 Hz), 1.46 (3H, t, J=6.9 Hz), 1.42-1.32 (1H, m), 0.69-0.62
(2H, m), 0.40-0.35 (2H, m)
Example 134
1-(3-ethoxypyridin-2-yl)-3-[2-(3-isobutoxy-4-methoxyphenyl)oxazol-4-yl]pro-
pan-1-one
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.23 (1H, dd, J=4.5, 1.5 Hz),
7.56 (1H, dd, J=8.4, 2.1 Hz), 7.50 (1H, d, J=2.1 Hz), 7.45 (1H, s),
7.38-7.28 (2H, m), 6.90 (1H, d, J=8.4 Hz), 4.12 (2H, q, J=6.9 Hz),
3.90 (3H, s), 3.85 (2H, d, J=6.6 Hz), 3.50 (2H, t, J=6.9 Hz), 3.02
(2H, t, J=6.9 Hz), 2.19 (2H, qt, J=6.6 Hz), 1.47 (3H, t, J=6.9 Hz),
1.05 (6H, d, J=6.6 Hz)
Example 135
A 5 g quantity of methyl 3-[2-(3-benzyloxy-4-methoxy
phenyl)oxazol-4-yl]propionate obtained in Reference Example 48 and
3.2 g of methyl 3-methylpicolinate were dissolved in 150 ml of
dimethoxyethane. While stirring the solution with ice cooling 1.2 g
of sodium hydride was added thereto and further stirred. The
reaction mixture was heated and refluxed for 4 hours. At the
completion of the reaction, a saturated aqueous ammonium chloride
solution was added to the mixture while stirring with ice cooling,
and the mixture was further stirred. After stirring the reaction
mixture for 30 minutes, water was added thereto and ethyl acetate
extraction was performed. The organic layer was washed twice with
water, and concentrated under reduced pressure. The obtained
residue was purified by silica gel column chromatography
(n-hexane:ethyl acetate=2:1), thereby yielding 5.5 g of colorless
oily substance methyl
2-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-(3-methylpyridin-2-
-yl)-3-oxopropionate.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.49 (1H, dd, J=4.8, 1.2 Hz),
7.59-7.28 (10H, m), 6.91 (1H, d, J=9.0 Hz), 5.23-5.16 (3H, m), 3.91
(3H, s), 3.65 (3H, s), 3.37-3.18 (2H, m) 2.59 (3H, s)
Example 136
A 5.5 g quantity of methyl 2-[2-(3-benzyloxy-4-methoxy
phenyl)oxazol-4-ylmethyl]-3-(3-methylpyridin-2-yl)-3-oxopropionate
obtained in Example 135 was dissolved in 20 ml of ethanol, 80 ml of
a 5N aqueous hydrochloric acid solution was added thereto, and the
mixture was stirred with heating at 80.degree. C. for 1.5 hours.
While stirring with ice cooling, the reaction mixture was
neutralized with 5 N aqueous sodium hydroxide solution, and ethyl
acetate extraction was performed. The organic layer was washed
twice with water, concentrated under reduced pressure, and the
obtained crude crystals were recrystallized with a mixture of 20 ml
of ethanol and 40 ml of n-hexane, thereby yielding 1.92 g of pale
yellow powdery 3-[2-(3-hydroxy-4-methoxy
phenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.49 (1H, dd, J=4.5, 1.2 Hz),
7.60-7.51 (3H, m), 7.44 (1H, d, J=0.9 Hz), 7.41-7.29 (1H, m), 6.89
(1H, dd, J=7.8, 1.2 Hz), 5.68 (1H, s), 3.93 (3H, s), 3.58 (2H, t,
J=7.5 Hz), 3.00 (2H, t, J=7.5 Hz), 2.57 (3H, s)
Example 137
A 0.3 g quantity of
3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)prop-
an-1-one obtained in Example 136 and 0.4 ml of
1,8-diazabicyclo[5,4,0]undec-7-ene were dissolved in 5 ml of
ethanol, 0.24 g of (bromomethyl)cyclopropane was added thereto, and
the mixture was heated and refluxed for 4.5 hours. After standing
to cool, water was added to the reaction mixture, and ethyl acetate
extraction was performed. The extract was washed twice with water,
the organic layer was then concentrated under reduced pressure, and
the obtained residue was purified by silica gel column
chromatography (n-hexane:ethyl acetate=2:1), thereby yielding 0.2 g
of white powdery
3-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methyl
pyridin-2-yl)propan-1-one.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.50 (1H, dd, J=4.5, 1.2 Hz),
7.60-7.54 (2H, m), 7.49 (1H, d, J=1.8 Hz), 7.45 (1H, s), 7.34-7.29
(1H, m), 6.91 (1H, d, J=8.7 Hz), 3.94-3.91 (5H, m), 3.60 (2H, t,
J=7.5 Hz), 3.00 (2H, t, J=7.5 Hz), 2.57 (3H, s), 1.40-1.32 (1H, m),
0.69-0.62 (2H, m), 0.41-0.35 (2H, m)
Example 138
A 0.23 g quantity of 3-[2-(3-hydroxy-4-methoxy
phenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one obtained
in Example 136 and 0.3 ml of 1,8-diazabicyclo[5,4,0]undec-7-ene
were dissolved in 5 ml of ethanol, 0.21 g of ethyl iodide was added
thereto, and the mixture was heated and refluxed for 4 hours. After
standing to cool, water was added to the reaction mixture, and
ethyl acetate extraction was performed. The extract was washed
twice with water, the organic layer was then concentrated under
reduced pressure, and the obtained residue was purified by silica
gel column chromatography (n-hexane:ethyl acetate=2:1), thereby
yielding 0.17 g of white powdery
3-[2-(3-ethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propa-
n-1-one.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.24 (1H, d, J=4.2 Hz), 7.58-7.55
(2H, m), 7.51 (1H, d, J=2.1 Hz), 7.45 (1H, s), 6.90 (1H, d, J=8.4
Hz), 4.19 (2H, q, J=7.2 Hz), 3.91 (3H, s), 3.59 (2H, t, J=7.2 Hz),
3.00 (2H, t, J=7.2 Hz), 2.57 (3H, s), 1.49 (3H, t, J=7.2 Hz)
Example 139
A 0.3 g quantity of
3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)prop-
an-1-one obtained in Example 136 and 0.4 ml of
1,8-diazabicyclo[5,4,0]undec-7-ene were dissolved in 5 ml of
ethanol, 0.23 g of 2-bromopropane was added thereto, and the
mixture was heated and refluxed for 4.5 hours. After standing to
cool, water was added to the reaction mixture, and ethyl acetate
extraction was performed. The extract was washed twice with water,
the organic layer was then concentrated under reduced pressure, and
the obtained residue was purified by silica gel column
chromatography (n-hexane:ethyl acetate=2:1), thereby yielding 0.16
g of white powdery
3-[2-(3-isopropoxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)p-
ropan-1-one.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.50 (1H, dd, J=4.5, 1.2 Hz),
7.59-7.53 (3H, m), 7.45 (1H, s), 7.34-7.31 (1H, m), 6.91 (1H, d,
J=8.7 Hz), 4.65 (1H, sept., J=6.0 Hz), 3.89 (3H, s), 3.59 (2H, t,
J=7.5 Hz), 3.00 (2H, t, J=7.5 Hz), 2.62 (3H, s), 1.39 (6H, d, J=6.0
Hz)
Example 140
A 0.3 g quantity of
3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)prop-
an-1-one obtained in Example 136 and 0.3 ml of
1,8-diazabicyclo[5,4,0]undec-7-ene were dissolved in 6 ml of
ethanol, 0.22 g of allyl bromide was added thereto, and the mixture
was heated and refluxed for 4 hours. After standing to cool, water
was added to the reaction mixture, and ethyl acetate extraction was
performed. The extract was washed twice with water, the organic
layer was then concentrated under reduced pressure, and the
obtained residue was purified by silica gel column chromatography
(n-hexane:ethyl acetate=2:1), thereby yielding 0.18 g of white
powdery
3-[2-(3-allyloxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)pro-
pan-1-one.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.51-8.48 (1H, m), 7.60-7.56 (2H,
m), 7.52 (1H, d, J=2.1 Hz), 7.45 (1H, s), 7.34-7.29 (1H, m), 6.92
(1H, d, J=8.7 Hz), 6.16-6.05 (1H, m), 5.48-5.28 (2H, m), 4.69-4.66
(2H, m), 3.92 (3H, s), 3.60 (2H, t, J=7.2 Hz), 3.00 (2H, t, J=7.2
Hz), 2.57 (3H, s)
Example 141
A 0.15 g quantity of 3-[2-(3-hydroxy-4-methoxy
phenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one obtained
in Example 136 and 0.15 ml of 1,8-diazabicyclo[5,4,0]undec-7-ene
were dissolved in 5 ml of ethanol, 0.13 g of
(bromomethyl)cyclobutane was added thereto, and the mixture was
heated and refluxed overnight. After standing to cool, water was
added to the reaction mixture, and ethyl acetate extraction was
performed. The extract was washed twice with water, the organic
layer was then concentrated under reduced pressure, and the
obtained residue was purified by silica gel column chromatography
(n-hexane:ethyl acetate=2:1), thereby yielding 90 mg of white
powdery
3-[2-(3-cyclobutylmethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-
-2-yl)propan-1-one.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.50 (1H, dd, J=4.5, 1.2 Hz),
7.60-7.51 (3H, m), 7.45 (1H, d, J=2.1 Hz), 7.34-7.29 (1H, m), 6.89
(1H, d, J=8.7 Hz), 4.07 (2H, d, J=6.9 Hz), 3.89 (3H, s), 3.60 (2H,
t, J=7.5 Hz), 3.01 (2H, t, J=7.5 Hz), 2.89-2.83 (1H, m), 2.57 (3H,
s), 2.22-2.13 (2H, m), 2.00-1.84 (4H, m)
Using
3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-y-
l)propan-1-one obtained in Example 136, compounds of Examples 142
to 154 were obtained in the same manner as in Example 137.
Example 142
3-[2-(3-isobutoxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methyl
pyridin-2-yl)propan-1-one
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.50 (1H, dd, J=4.5, 1.2 Hz),
7.60-7.53 (2H, m), 7.50 (1H, d, J=1.8 Hz), 7.45 (1H, s), 7.34-7.28
(1H, m), 6.90 (1H, d, J=8.4 Hz), 3.90 (3H, s), 3.84 (2H, d, J=6.9
Hz), 3.60 (2H, t, J=7.8 Hz), 3.01 (2H, t, J=7.8 Hz), 2.57 (3H, s),
2.20 (1H, qt, J=6.9 Hz), 1.05 (6H, d, J=6.9 Hz)
Example 143
3-[2-(4-methoxy-3-propoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propa-
n-1-one
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.50 (1H, dd, J=4.5, 1.2 Hz),
7.59-7.54 (2H, m), 7.51 (1H, d, J=1.8 Hz), 7.50 (1H, s), 7.34-7.29
(1H, m), 6.90 (1H, d, J=8.4 Hz), 4.05 (2H, t, J=6.9 Hz), 3.91 (3H,
s), 3.60 (2H, t, J=7.5 Hz), 3.01 (2H, t, J=7.5 Hz), 2.57 (3H, s),
1.90 (2H, qt, J=6.9 Hz), 1.24 (3H, t, J=6.9 Hz)
Example 144
3-[2-(3-cyclopentyloxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methyl
pyridine-2-yl)propane-1-one
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.50 (1H, dd, J=4.5, 1.2 Hz),
7.59-7.50 (3H, m), 7.44 (1H, d, J=1.2 Hz), 7.34-7.31 (1H, m), 6.89
(1H, d, J=8.4 Hz), 4.90-4.84 (1H, m), 3.88 (3H, s), 3.59 (2H, t,
J=7.2 Hz), 3.00 (2H, t, J=7.2 Hz), 2.57 (3H, s), 2.03-1.80 (6H, m),
1.64-1.58 (2H, m)
Example 145
3-[2-(4-methoxy-3-(2-propenyloxy)phenyl)oxazol-4-yl]-1-(3-methylpyridin-2--
yl)propan-1-one
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.50 (1H, d, J=4.5 Hz), 7.67-7.63
(2H, m), 7.58 (1H, d, J=8.1 Hz), 7.46 (1H, s), 7.34-7.30 (1H, m),
6.93 (1H, dd, J=6.6, 2.4 Hz), 4.82 (2H, d, J=2.4 Hz), 3.92 (3H, s),
3.60 (2H, t, J=7.2 Hz), 3.01 (2H, t, J=7.2 Hz), 2.58 (3H, s), 2.53
(1H, t, J=2.4 Hz)
Example 146
3-[2-(3-(3-butenyloxy)-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-y-
l)propan-1-one
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.50 (1H, dd, 1.5 Hz), 7.59-7.55
(2H, m), 7.52 (1H, d, J=2.1 Hz), 7.45 (1H, d, J=2.1 Hz), 7.34-7.29
(1H, m), 5.97-5.85 (1H, m), 5.23-5.09 (2H, m), 4.14 (2H, t, J=6.9
Hz), 3.91 (3H, s), 3.60 (2H, t, J=7.5 Hz), 3.00 (2H, t, J=7.5 Hz),
2.68-2.57 (5H, m)
Example 147
3-[2-(3-butoxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-
-1-one
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.50 (1H, d, J=4.8 Hz), 7.59-7.51
(3H, m), 7.45 (1H, s), 7.34-7.30 (1H, m), 6.90 (1H, d, J=8.7 Hz),
4.09 (2H, t, J=6.6 Hz), 3.90 (3H, s), 3.60 (2H, t, J=7.2 Hz), 3.01
(2H, t, J=7.2 Hz), 2.57 (3H, s), 1.86 (2H, td, J=7.2, 6.6 Hz),
1.56-1.45 (2H, m), 0.99 (3H, t, J=7.2 Hz)
Example 148
3-[2-(3-cyclohexylmethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin--
2-yl)propan-1-one
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.50 (1H, d, J=4.5 Hz), 7.61-7.53
(2H, m), 7.49 (1H, d, J=1.8 Hz), 7.45 (1H, s), 7.34-7.28 (1H, m),
6.89 (1H, d, J=8.7 Hz), 3.90-3.86 (5H, m), 3.60 (2H, t, J=7.5 Hz),
3.01 (2H, t, J=7.5 Hz), 2.57 (3H, s), 1.94-1.85 (3H, m), 1.79-1.57
(3H, m), 1.38-0.88 (5H, m)
Example 149
3-[2-(4-methoxy-3-(4-pentenyloxy)phenyl)oxazol-4-yl]-1-(3-methylpyridin-2--
yl)propan-1-one
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.50 (1H, dd, J=4.5, 1.2 Hz),
7.59-7.54 (2H, m), 7.51 (1H, d, J=2.1 Hz), 7.45 (1H, s), 7.34-7.29
(1H, m), 6.91 (1H, d, J=8.4 Hz), 5.91-5.80 (1H, m), 5.11-4.97 (2H,
m), 4.10 (2H, d, J=6.6 Hz), 3.91 (3H, s), 3.60 (2H, t, J=7.5 Hz),
3.01 (2H, t, J=7.5 Hz), 2.57 (3H, s), 2.30-2.22 (2H, m), 2.05-1.92
(2H, m)
Example 150
3-[2-(4-methoxy-3-phenethyloxyphenyl)oxazol-4-yl]-1-(3-methyl
pyridin-2-yl)propan-1-one
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.48 (1H, dd, J=4.5, 0.9 Hz),
7.60-7.49 (3H, m), 7.43 (1H, s), 7.35-7.20 (6H, m), 6.91 (1H, d,
J=8.7 Hz), 4.27 (2H, t, J=7.5 Hz), 3.91 (3H, s), 3.58 (2H, t, J=7.2
Hz), 3.19 (2H, t, J=7.5 Hz), 3.00 (2H, t, J=7.2 Hz), 2.55 (3H,
s)
Example 151
3-{2-[4-methoxy-3-(3-phenylpropoxy)phenyl]oxazol-4-yl}-1-(3-methylpyridin--
2-yl)propan-1-one
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.50 (1H, dd, J=4.5, 1.2 Hz),
7.58 (1H, d, J=2.1 Hz), 7.55 (1H, d, J=2.1 Hz), 7.49 (1H, d, J=2.1
Hz), 7.44 (1H, s), 7.34-7.15 (6H, m), 6.91 (1H, d, J=8.4 Hz), 4.11
(2H, t, J=6.6 Hz), 3.92 (3H, s), 3.60 (2H, t, J=7.5 Hz), 3.00 (2H,
t, J=7.5 Hz), 2.84 (2H, t, J=7.5 Hz), 2.57 (3H, s), 2.20 (2H, tt,
J=7.5, 6.6 Hz)
Example 152
Using 0.5 g of cyclopentylmethyl methanesulfonate obtained in
Reference Example 52 and 0.2 g of
3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)prop-
an-1-one obtained in Example 136, 90 mg of white powdery
3-[2-(3-cyclopentylmethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methyl
pyridin-2-yl)propan-1-one was obtained in the same manner as in
Example 137.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.49 (1H, d, J=3.9 Hz), 7.59-7.50
(3H, m), 7.45 (1H, s), 7.34-7.29 (1H, m), 6.90 (1H, d, J=8.4 Hz),
3.95 (2H, d, J=7.2 Hz), 3.90 (3H, s), 3.60 (2H, t, J=7.5 Hz), 3.01
(2H, t, J=7.5 Hz), 2.57 (3H, s), 2.54-2.41 (1H, m), 1.91-1.82 (2H,
m), 1.68-1.56 (4H, m), 1.42-1.24 (2H, m)
Example 153
Using 0.16 g of 2-cyclopropylethyl methanesulfonate obtained in
Reference Example 50 and 0.15 g of
3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)prop-
an-1-one obtained in Example 136, 0.1 g of white powdery
3-{2-[3-(2-cyclopropylethoxy)-4-methoxyphenyl]oxazol-4-yl}-1-(3-methyl
pyridin-2-yl)propan-1-one was obtained in the same manner as in
Example 137.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.50 (1H, dd, 1.5 Hz), 7.60-7.54
(3H, m), 7.46 (1H, s), 7.35-7.27 (1H, m), 6.91 (1H, d, J=8.1 Hz),
4.18 (2H, t, J=6.9 Hz), 3.91 (3H, s), 3.61 (2H, t, J=7.5 Hz), 3.02
(2H, t, J=7.5 Hz), 2.58 (3H, s), 1.78 (2H, q, J=6.9 Hz), 0.91-0.80
(1H, m), 0.53-0.46 (2H, m), 0.16-0.11 (2H, m)
Example 154
Using 0.19 g of 2-cyclopentylethyl methanesulfonate obtained in
Reference Example 51 and 0.15 g of
3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)prop-
an-1-one obtained in Example 136, 0.13 g of white powdery
3-{2-[3-(2-cyclopentylethoxy)-4-methoxyphenyl]oxazol-4-yl}-1-(3-methyl
pyridin-2-yl)propan-1-one was obtained in the same manner as in
Example 137.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.50 (1H, dd, J=4.5, 1.2 Hz),
7.60-7.50 (3H, m), 7.45 (1H, s), 7.34-7.30 (1H, m), 6.90 (1H, d,
J=8.4 Hz), 4.10 (2H, t, J=6.9 Hz), 3.92 (3H, s), 3.60 (2H, t, J=7.5
Hz), 3.01 (2H, t, J=7.5 Hz), 2.57 (3H, s), 2.01-1.79 (5H, m),
1.67-1.50 (5H, m), 1.24-1.12 (2H, m)
Example 155
A 0.23 g quantity of
3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)prop-
an-1-one obtained in Example 136 and 0.28 g of potassium carbonate
were dissolved in 5 ml of dimethylformamide. A 0.29 g quantity of
1,1,1-trifluoro-2-iodoethane was added thereto, and the mixture was
stirred with heating at 80.degree. C. overnight. The reaction
mixture was allowed to cool, water was then added thereto, and
extraction was performed with ethyl acetate. After washing with
water twice, the organic layer was concentrated under reduced
pressure. The obtained residue was purified by silica gel column
chromatography (dichloromethane:ethyl acetate=1:1) to give 0.14 g
of white powdery
3-{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-yl}-1-(3-methylp-
yridin-2-yl)propan-1-one.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.50 (1H, dd, J=4.5, 0.9 Hz),
7.70 (1H, dd, J=8.4, 2.1 Hz), 7.60-7.56 (2H, m), 7.46 (1H, d, J=2.1
Hz), 7.35-7.30 (1H, m), 6.96 (1H, d, J=8.4 Hz), 4.45 (2H, q, J=8.4
Hz), 3.92 (3H, s), 3.60 (2H, t, J=7.5 Hz), 3.00 (2H, t, J=7.5 Hz),
2.57 (3H, s)
Example 156
Using 0.1 g of
3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)prop-
an-1-one obtained in Example 136, 45 mg of pale yellow powdery
3-{2-[4-methoxy-3-(3-methyl-2-butenyloxy)phenyl]oxazol-4-yl}-1-(3-methylp-
yridin-2-yl)propan-1-one was obtained in the same manner as in
Example 155.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.50 (1H, dd, J=4.5, 1.2 Hz),
7.59-7.52 (3H, m), 7.45 (1H, s), 7.34-7.29 (1H, m), 6.90 (1H, d,
J=8.4 Hz), 5.58-5.52 (1H, m), 4.64 (2H, d, J=6.9 Hz), 3.91 (3H, s),
3.60 (2H, t, J=7.5 Hz), 3.01 (2H, t, J=7.5 Hz), 2.57 (3H, s), 1.78
(3H, d, J=0.9 Hz), 1.77 (3H, s)
Example 157
Using 0.6 g of
3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)prop-
an-1-one obtained in Example 136, 0.31 g of white powdery
3-{2-[3-(2-cyclohexenyloxy)-4-methoxyphenyl]oxazol-4-yl}-1-(3-methylpyrid-
in-2-yl)propan-1-one was obtained in the same manner as in Example
155.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.50 (1H, dd, J=4.5, 1.2 Hz),
7.60-7.56 (3H, m), 7.45 (1H, s), 7.34-7.29 (1H, m), 6.91 (1H, d,
J=9.0 Hz), 5.99-5.88 (2H, m), 4.88 (1H, br s), 3.89 (3H, s), 3.60
(2H, t, J=7.2 Hz), 3.01 (2H, t, J=7.2 Hz), 2.57 (3H, s), 2.17-1.84
(5H, m), 1.71-1.61 (1H, m)
Example 158
A 0.3 g quantity of
3-{2-[3-(2-cyclohexenyloxy)-4-methoxyphenyl]oxazol-4-yl}-1-(3-methylpyrid-
in-2-yl)propan-1-one obtained in Example 157 was dissolved in 20 ml
of ethanol. A 50 mg quantity of 10% palladium-carbon powder was
added thereto, and the mixture was stirred at room temperature for
2 hours. The catalyst was removed by filtration, and the filtrate
was then concentrated. The obtained residue was purified by silica
gel column chromatography (n-hexane:ethyl acetate=3:1) to give 0.2
g of pale yellow oily
3-[2-(3-cyclohexyloxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridi-
n-2-yl)propan-1-one.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.50 (1H, d, J=4.5 Hz), 7.59-7.54
(3H, m), 7.45 (1H, s), 7.34-7.30 (1H, m), 6.91 (1H, d, J=8.1 Hz),
4.35-4.25 (1H, m), 3.89 (3H, s), 3.60 (2H, t, J=7.5 Hz), 3.01 (2H,
t, J=7.5 Hz), 2.57 (3H, s), 2.07-2.02 (2H, m), 1.84-1.80 (2H, m),
1.60-1.51 (4H, m), 1.43-1.23 (2H, m)
Example 159
A 0.26 g quantity of
3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)prop-
an-1-one obtained in Example 136 was dissolved in 10 ml of
tetrahydrofuran. To the obtained solution were added 0.2 g of
2-hydroxyindane, 0.75 ml of diisopropyl azodicarboxylate (40%
toluene solution) and 0.31 g of tri(n-butyl)phosphine, and the
mixture was stirred at 50.degree. C. After 3 hours, 0.2 g of
2-hydroxyindan, 0.75 ml of diisopropyl azodicarboxylate (40%
toluene solution) and 0.31 g of tri(n-butyl)phosphine were further
added thereto, and the mixture was stirred at 50.degree. C.
overnight. The reaction mixture was concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (n-hexane:ethyl acetate:dichloromethane=1:1:1), and
recrystallized from acetone/diisopropyl ether to give 0.13 g of
colorless powdery
3-{2-[3-(indan-2-yloxy)-4-methoxyphenyl]oxazol-4-yl}-1-(3-methylp-
yridin-2-yl)propan-1-one.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.51 (1H, br d, J=4.8 Hz),
7.62-7.16 (9H, m), 6.91 (1H, d, J=8.7 Hz), 5.29 (1H, tt, J=6.6, 3.9
Hz), 3.85 (3H, s), 3.63 (2H, t, J=7.2 Hz), 3.45 (2H, dd, J=16.8,
6.6 Hz), 3.26 (2H, dd, J=16.8, 3.9 Hz), 3.01 (2H, t, J=7.2 Hz),
2.58 (3H, s)
Example 160
A 2 g quantity of methyl
3-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-yl]propionate obtained
in Reference Example 48 and 1.5 g of methyl picolinate were
dissolved in 40 ml of dimethoxyethane. A 0.33 g quantity of sodium
hydride was added thereto with ice-cooling and stirring, and
stirring was further continued. The reaction mixture was heated and
refluxed for 2 hours. After the reaction, an aqueous saturated
ammonium chloride solution was added thereto with ice-cooling and
stirring, and the mixture was stirred. The reaction mixture was
stirred for 30 minutes, water was then added thereto, and
extraction was performed with ethyl acetate. The organic layer was
washed twice with water and concentrated by removing the solvent
under reduced pressure. The obtained residue was purified by silica
gel column chromatography (n-hexane:ethyl acetate=3:1) to give 2 g
of colorless oily methyl
2-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-oxo-3-pyridin-2-yl-
propionate.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.67 (1H, dd, J=4.2, 0.9 Hz),
8.07 (1H, dd, J=7.8, 2.1 Hz), 7.83 (1H, td, J=7.8, 1.8 Hz),
7.55-7.30 (9H, m), 6.90 (1H, d, J=9.0 Hz), 5.29 (1H, t, J=7.8 Hz),
5.16 (2H, s), 3.91 (3H, s), 3.66 (3H, s), 3.36-3.28 (2H, m)
Example 161
Using 2 g of methyl
2-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-oxo-3-(pyridin-2-y-
l)propionate obtained in Example 160, 0.48 g of white powdery
3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(pyridin-2-yl)propan-1-one
was obtained in the same manner as in Example 136.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.67 (1H, dd, J=4.2, 0.9 Hz),
8.05 (1H, dd, J=7.8, 2.1 Hz), 7.83 (1H, td, J=7.8, 1.8 Hz),
7.55-7.43 (4H, m), 6.88 (1H, dd, J=7.8, 2.1 Hz), 5.72 (1H, s), 3.93
(3H, s), 3.64 (2H, t, J=7.5 Hz), 3.03 (2H, t, J=7.5 Hz)
Example 162
A 0.15 g quantity of
3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(pyridin-2-yl)propan-1-one
obtained in Example 161 and 0.2 ml of
1,8-diazabicyclo[5,4,0]undec-7-ene were dissolved in 5 ml of
ethanol. A 0.14 g quantity of (bromomethyl)cyclobutane was added
thereto, and the mixture was heated and refluxed overnight. The
reaction mixture was allowed to cool, water was then added thereto,
and extraction was performed with ethyl acetate. After washing with
water twice, the organic layer was concentrated under reduced
pressure. The obtained residue was purified by silica gel column
chromatography (dichloromethane:ethyl acetate=5:1) to give 50 mg of
white powdery
3-[2-(3-cyclobutylmethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(pyridin-
-2-yl)propan-1-one.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.68 (1H, d, J=4.5 Hz), 8.05 (1H,
d, J=7.8 Hz), 7.83 (1H, td, J=7.8, 1.8 Hz), 7.58-7.44 (4H, m), 6.90
(1H, d, J=8.4 Hz), 4.07 (2H, d, J=6.9 Hz), 3.89 (3H, s), 3.65 (2H,
t, J=7.5 Hz), 3.05 (2H, t, J=7.5 Hz), 2.94-2.81 (1H, m), 2.24-2.04
(2H, m), 2.00-1.81 (4H, m)
Example 163
Using 0.3 g of
3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(pyridin-2-yl)propan-1-one
obtained in Example 161, 0.28 g of white powdery
3-[2-(4-methoxy-3-(4-pentenyloxy)phenyl)oxazol-4-yl]-1-(pyridin-2-yl)prop-
an-1-one was obtained in the same manner as in Example 102.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.69 (1H, dd, J=4.2, 1.5 Hz),
8.05 (1H, d, J=7.8 Hz), 7.85 (1H, t, J=7.8 Hz), 7.60-7.46 (4H, m),
6.91 (1H, d, J=8.4 Hz), 5.92-5.83 (1H, m), 5.11-4.99 (2H, m), 4.11
(2H, d, J=6.9 Hz), 3.91 (3H, s), 3.65 (2H, t, J=7.5 Hz), 3.05 (2H,
t, J=7.5 Hz), 2.28-2.23 (2H, m), 1.98 (2H, t, J=7.5 Hz)
Example 164
A 10 g quantity of
2-(3-benzyloxy-4-methoxyphenyl)-4-chloromethyloxazole obtained in
Reference Example 5 and 10.7 g of 1-(2-allyloxyphenyl)ethanone
obtained in Reference Example 53 were dissolved in 200 ml of
tetrahydrofuran. A 1.82 g quantity of sodium hydride was added
thereto with ice-cooling and stirring, and stirring was further
continued. The reaction mixture was heated and refluxed for 4
hours. After the reaction, an aqueous saturated ammonium chloride
solution was added thereto with ice-cooling and stirring, and the
mixture was stirred. After stirring for 30 minutes, water was added
thereto, and extraction was performed with ethyl acetate. The
organic layer was washed with water twice and concentrated by
removing the solvent under reduced pressure. The obtained residue
was purified by silica gel column chromatography (n-hexane:ethyl
acetate=3:1) to give 1.4 g of white powdery
1-(2-allyloxyphenyl)-3-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-y-
l]propan-1-one.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.70 (1H, dd, J=7.8, 1.8 Hz),
7.62-7.58 (2H, m), 7.49-7.30 (7H, m), 7.02-6.91 (3H, m), 6.12-6.02
(1H, m), 5.42 (1H, dd, J=17.4, 1.5 Hz), 5.30 (1H, dd, J=10.5, 1.5
Hz), 5.19 (2H, s), 4.65-4.62 (2H, m), 3.92 (3H, s), 3.42 (2H, t,
J=7.2 Hz), 2.99 (2H, t, J=7.2 Hz)
Example 165
Using 1.4 g of
1-(2-allyloxyphenyl)-3-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-yl]propan-
-1-one obtained in Example 164, 0.55 g of pale yellow oily
3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-hydroxyphenyl)propan-1--
one was obtained in the same manner as in Example 101.
.sup.1H-NMR (CDCl.sub.3) .delta.: 12.5 (1H, s), 7.81 (1H, dd,
J=7.8, 1.5 Hz), 7.57-7.30 (4H, m), 6.98 (1H, d, J=8.1 Hz),
6.92-6.86 (2H, m), 5.73 (1H, br s), 3.94 (3H, s), 3.44 (2H, t,
J=7.5 Hz), 3.02 (2H, t, J=7.5 Hz)
Example 166
Using 0.5 g of
3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-hydroxyphenyl)propan-1--
one obtained in Example 165, 0.61 g of white powdery
3-[2-(3-allyloxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-allyloxyphenyl)propan--
1-one was obtained in the same manner as in Example 111.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.70 (1H, dd, J=7.5, 2.1 Hz),
7.58 (1H, dd, J=8.1, 2.1 Hz), 7.52 (1H, d, J=2.1 Hz), 7.45-7.40
(2H, m), 7.02-6.90 (3H, m), 6.16-6.03 (2H, m), 5.47-5.27 (4H, m),
4.68-4.62 (4H, m), 3.92 (3H, s), 3.42 (2H, t, J=6.9 Hz), 2.99 (2H,
t, J=6.9 Hz)
Example 167
Using 1.1 g of methyl
3-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-yl]propionate obtained
in Reference Example 48, 1 g of yellow oily methyl
2-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-(2-methoxyphenyl)--
3-oxopropionate was obtained in the same manner as in Example
100.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.71 (1H, dd, J=7.8, 1.8 Hz),
7.57-7.53 (3H, m), 7.48-7.30 (6H, m), 6.97 (1H, t, J=7.2 Hz), 6.91
(2H, d, J=7.8 Hz), 5.17 (2H, s), 4.99 (1H, t, J=6.9 Hz), 3.92 (3H,
s), 3.90 (3H, s), 3.69 (3H, s), 3.27-3.19 (2H, m)
Example 168
Using 1 g of methyl
2-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-(2-methoxyphenyl)--
3-oxopropionate obtained in Example 167, 0.63 g of white powdery
3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-methoxyphenyl)propan-1--
one was obtained in the same manner as in Example 101.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.70 (1H, dd, J=8.4, 2.1 Hz),
7.56-7.52 (2H, m), 7.44-7.41 (2H, m), 6.99-6.87 (3H, m), 3.95 (3H,
s), 3.89 (3H, s), 3.38 (2H, t, J=7.2 Hz), 2.98 (2H, t, J=7.2
Hz)
Example 169
Using 0.22 g of
3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-methoxyphenyl)propan-1--
one obtained in Example 168, 90 mg of colorless oily
3-[2-(3-isopropoxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-methoxyphenyl)propan-
-1-one was obtained in the same manner as in Example 102.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.70 (1H, d, J=7.5 Hz), 7.57 (1H,
d, J=8.1 Hz), 7.54 (1H, s), 7.47-7.40 (2H, m), 7.01-6.89 (3H, m),
4.67-4.62 (1H, m), 3.91 (6H, s), 3.38 (2H, t, J=7.2 Hz), 3.00 (2H,
t, J=7.2 Hz), 1.39 (6H, d, J=6.3 Hz)
Using
3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-methoxyphenyl)pro-
pan-1-one obtained in Example 168, compounds of Examples 170 to 173
were obtained in the same manner as in Example 102.
Example 170
3-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-methoxyphenyl-
)propan-1-one
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.69-7.40 (4H, m), 6.99-6.89 (4H,
m), 3.94-3.89 (8H, m), 3.37 (2H, t, J=7.2 Hz), 3.01 (2H, t, J=7.2
Hz), 1.40-1.35 (1H, m), 0.67-0.65 (2H, m), 0.38-0.36 (2H, m)
Example 171
3-[2-(3-cyclopentyloxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-methoxyphenyl)pro-
pan-1-one
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.70 (1H, dd, J=7.5, 1.8 Hz),
7.56 (1H, dd, J=8.4, 2.1 Hz), 7.51 (1H, s), 7.43 (1H, td, J=8.4,
1.8 Hz), 6.99-6.88 (3H, m), 4.48 (1H, br s), 3.89 (3H, s), 3.88
(3H, s), 3.38 (2H, t, J=6.6 Hz), 2.98 (2H, t, J=6.6 Hz), 2.04-1.85
(4H, m), 1.63-1.55 (4H, m)
Example 172
3-[2-(3-ethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-methoxyphenyl)propan-1-on-
e
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.70 (1H, dd, J=7.5, 1.8 Hz),
7.57 (1H, dd, J=8.1, 2.1 Hz), 7.51 (1H, d, J=1.8 Hz), 7.47-7.41
(2H, m), 7.01-6.89 (3H, m), 4.18 (2H, q, J=7.8 Hz), 3.94 (3H, s),
3.90 (3H, s), 3.38 (2H, t, J=6.6 Hz), 2.99 (2H, t, J=6.6 Hz), 1.49
(3H, t, J=7.8 Hz)
Example 173
3-[2-(3-isobutoxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-methoxy
phenyl)propan-1-one
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.70 (1H, dd, J=7.5, 1.8 Hz),
7.58-7.36 (4H, m), 7.01-6.89 (3H, m), 3.90 (6H, s), 3.84 (2H, d,
J=6.6 Hz), 3.38 (2H, t, J=6.9 Hz), 2.99 (2H, t, J=6.9 Hz),
2.22-2.10 (1H, m), 1.05 (6H, d, J=6.6 Hz)
Using
3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-methoxyphenyl)pro-
pan-1-one obtained in Example 168, compounds of Examples 174 to 175
were obtained in the same manner as in Example 111.
Example 174
3-[2-(3-allyloxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-methoxyphenyl)propan-1--
one
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.70 (1H, dd, J=7.5, 1.8 Hz),
7.59 (1H, dd, J=8.4, 1.8 Hz), 7.52 (1H, d, J=1.8 Hz), 7.48-7.41
(2H, m), 7.02-6.90 (3H, m), 6.12-6.07 (1H, m), 5.43 (1H, dd, J=17,
1.5 Hz), 5.31 (1H, d, J=10 Hz), 4.68 (2H, d, J=5.4 Hz), 3.92 (3H,
s), 3.90 (3H, s), 3.38 (2H, t, J=7.2 Hz), 2.99 (2H, t, J=7.2
Hz)
Example 175
1-(2-methoxyphenyl)-3-{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol-
-4-yl}propan-1-one
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.69 (1H, dd, J=7.5, 1.8 Hz),
7.60 (1H, d, J=1.8 Hz), 7.48-7.42 (2H, m), 7.02-6.95 (3H, m), 4.43
(2H, q, J=8.1 Hz), 3.92 (3H, s), 3.90 (3H, s), 3.38 (2H, t, J=6.9
Hz), 2.99 (2H, t, J=6.9 Hz)
Example 176
A 0.4 g quantity of sodium hydride was suspended in 20 ml of
tetrahydrofuran, and 1.13 g of 1-(2-benzyloxy)ethanone and 1.46 g
of 4-chloromethyl-2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazole
obtained in Reference Example 11 were successively added thereto
with ice-cooling. The mixture was stirred for 4 hours with heating
and refluxing. An aqueous saturated ammonium chloride solution was
added to the reaction mixture with ice cooling. After stirring for
15 minutes, water was added thereto, and extraction was performed
with ethyl acetate. Drying was performed with anhydrous magnesium
sulfate, and the solvent was removed. Purification was performed
using a silica gel column (n-hexane:ethyl acetate=4:1), and the
obtained compound was dissolved in 12 ml of ethanol. A 35 mg
quantity of 10% palladium-carbon powder was added thereto, and
stirring was performed under a hydrogen atmosphere overnight. The
catalyst was removed by filtration and the obtained filtrate was
concentrated. The residue was purified using a silica gel column
(n-hexane:ethyl acetate=4:1) to give 0.43 g of white powdery
3-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-hydroxy
phenyl)propan-1-one.
.sup.1H-NMR (CDCl.sub.3) .delta.: 12.2 (1H, s), 7.83 (1H, d, J=1.5
Hz), 7.80-7.44 (4H, m), 7.00-6.87 (3H, m), 3.94-3.92 (5H, m), 3.44
(2H, t, J=7.2 Hz), 3.03 (2H, t, J=7.2 Hz), 1.37-1.26 (1H, m),
0.70-0.65 (2H, m), 0.41-0.37 (2H, m)
Example 177
A 2 g quantity of 4-chloromethyl-2-(3-cyclopropyl
methoxy-4-methoxyphenyl)oxazole obtained in Reference Example 11
and 3.6 g of 1-(2-allyloxyphenyl)ethanone obtained in Reference
Example 53 were dissolved in 40 ml of tetrahydrofuran. A 0.55 g
quantity of sodium hydride was added thereto with ice-cooling and
stirring, and the mixture was stirred. The reaction mixture was
heated and refluxed for 6 hours. After the reaction completion, an
aqueous saturated ammonium chloride solution was added thereto with
ice-cooling, and the mixture was stirred. The reaction mixture was
stirred for 30 minutes, water was then added thereto, and
extraction was performed with ethyl acetate. The organic layer was
washed with water twice and concentrated by removing the solvent
under reduced pressure. The obtained residue was purified by silica
gel column chromatography (n-hexane:ethyl acetate=3:1) to give 0.5
g of while powdery
1-(2-allyloxyphenyl)-3-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)
oxazol-4-yl]propan-1-one.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.70 (1H, dd, J=7.8, 1.8 Hz),
7.57 (1H, dd, J=8.4, 2.1 Hz), 7.49 (1H, d, J=2.1 Hz), 7.45-7.39
(2H, m), 7.02-6.89 (3H, m), 6.09-6.02 (1H, m), 5.45-5.26 (2H, m),
4.65-4.62 (2H, m), 3.94-3.91 (5H, m), 3.42 (2H, t, J=7.2 Hz), 2.99
(2H, t, J=7.2 Hz), 1.45-1.35 (1H, m), 0.68-0.62 (2H, m), 0.40-0.36
(2H, m)
Example 178
Using 1.4 g of 4-chloromethyl-2-(3,4-diethoxyphenyl)oxazole
obtained in Reference Example 35 and 0.88 g of
1-(2-allyloxyphenyl)ethanone obtained in Reference Example 53, 0.42
g of white powdery
1-(2-allyloxyphenyl)-3-[2-(3,4-diethoxyphenyl)oxazol-4-yl]propan-1-one
was obtained in the same manner as in Example 177.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.69 (1H, dd, J=7.5, 2.1 Hz),
7.56-7.51 (2H, m), 7.45-7.39 (2H, m), 7.02-6.89 (3H, m), 6.14-6.01
(1H, m), 5.42 (1H, dd, J=17, 1.5 Hz), 5.29 (1H, dd, J=10.5, 1.5
Hz), 4.65-4.62 (2H, m), 4.20-4.10 (4H, m), 3.42 (2H, t, J=7.2 Hz),
2.99 (2H, t, J=7.2 Hz), 1.50 (6H, t, J=7.2 Hz)
Example 179
Using 0.31 g of 1-(2-chlorophenyl)ethanone and 0.59 g of
4-chloromethyl-2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazole
obtained in Reference Example 11, 0.11 g of colorless oily
1-(2-chlorophenyl)-3-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-yl-
]propan-1-one was obtained in the same manner as in Example
177.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.60-7.55 (2H, m), 7.49-7.43 (2H,
m), 7.40 (1H, s), 7.39-7.30 (2H, m), 6.91 (1H, d, J=8.7 Hz),
3.94-3.91 (5H, m), 3.36 (2H, t, J=6.9 Hz), 3.01 (2H, t, J=6.9 Hz),
1.37-1.29 (1H, m), 0.69-0.63 (2H, m), 0.40-0.37 (2H, m)
Example 180
Using 2 g of methyl 3-[2-(3,4-diethoxyphenyl)oxazol-4-yl]propionate
obtained in Reference Example 54 and 1.3 g of ethyl
3-methylpicolinate, 0.8 g of yellow oily methyl
2-[2-(3,4-diethoxyphenyl)oxazol-4-ylmethyl]-3-(3-methylpyridin-2-yl)-3-ox-
opropionate was obtained in the same manner as in Example 124.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.50 (1H, m), 7.60-7.40 (4H, m),
7.30 (1H, m), 6.88 (1H, d, J=8.4 Hz), 5.20 (1H, t, J=7.2 Hz),
4.20-4.05 (4H, m), 2.99 (3H, s), 3.35-3.20 (2H, m), 2.59 (3H, s),
1.47 (3H, t, J=6.9 Hz), 1.47 (3H, t, J=6.9 Hz)
Example 181
A 0.8 g quantity or methyl
2-[2-(3,4-diethoxyphenyl)oxazol-4-ylmethyl]-3-(3-methylpyridin-2-yl)-3-ox-
opropionate obtained in Example 180 was added to a mixture of 5 ml
acetic acid and 1.5 ml of concentrated hydrochloric acid, and the
resulting mixture was stirred at 110.degree. C. for 4 hours. After
cooling the obtained solution to room temperature, 30 ml of ethyl
acetate and 30 ml of saturated sodium hydrogen carbonate solution
were gradually added thereto with stirring, and stirring was
further continued. The organic layer was dried over anhydrous
magnesium sulfate, and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (ethyl
acetate:n-hexane=3:1), and further recrystallized from ethyl
acetate/n-hexane to give 0.28 g of white powdery
3-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-on-
e.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.49 (1H, m), 7.60-7.50 (3H, m),
7.44 (1H, s), 7.32 (1H, m), 6.90 (1H, d, J=8.1 Hz), 4.17 (2H, q,
J=6.9 Hz), 4.13 (2H, q, J=6.9 Hz), 3.51 (2H, t, J=7.2 Hz), 3.00
(2H, t, J=7.2 Hz), 2.57 (3H, s), 1.48 (3H, t, J=6.9 Hz), 1.47 (3H,
t, J=6.9 Hz)
Example 182
A 2 g quantity of methyl
3-[2-(3,4-diethoxyphenyl)oxazol-4-yl]propionate obtained in
Reference Example 54 and 1.5 g of ethyl 2-ethoxybenzoate were
dissolved in 10 ml of dimethylformamide. A 1.81 g quantity of
sodium t-pentoxide was added thereto with ice-cooling and stirring,
and the mixture was stirred for 30 minutes. The reaction mixture
was further stirred at room temperature for 5 hours, and ice was
added thereto. An aqueous saturated ammonium chloride solution was
added thereto, and the mixture was stirred. The reaction mixture
was stirred for 30 minutes, water was then added thereto, and
extraction was performed with ethyl acetate. The organic layer was
washed with water twice and concentrated by removing the solvent
under reduced pressure. The obtained residue was purified by silica
gel column chromatography (n-hexane:ethyl acetate=1:1). The
obtained yellow oily substance was added to a mixture of 5 ml of
acetic acid and 1.5 ml of concentrated hydrochloric acid, and the
resulting mixture was stirred at 110.degree. C. for 4 hours. After
cooling the mixture to room temperature, 30 ml of ethyl acetate and
30 ml of saturated sodium hydrogen carbonate solution were
gradually added thereto with stirring, and stirring was further
continued. The organic layer was dried over anhydrous magnesium
sulfate, and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (ethyl
acetate:n-hexane=3:1), and the obtained crude crystals were
recrystallized from ethyl acetate/n-hexane to give 0.46 g of white
powdery
3-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-one.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.70 (1H, dd, J=7.5, 2.1 Hz),
7.60-7.50 (2H, m), 7.45-7.35 (2H, m), 7.00-6.80 (2H, m), 4.17 (2H,
q, J=7.2 Hz), 4.13 (2H, q, J=7.2 Hz), 3.42 (2H, t, J=7.2 Hz), 2.99
(2H, t, J=7.2 Hz), 1.48 (3H, t, J=7.2 Hz), 1.48 (3H, t, J=7.2 Hz),
1.48 (3H, t, J=7.2 Hz)
Using methyl 3-[2-(3,4-diethoxyphenyl)oxazol-4-yl]propionate
obtained in Reference Example 54, compounds of Example 183 to 185
were obtained in the same manner as in Example 182.
Example 183
3-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-1-(3-ethoxypyridin-2-yl)propan-1-one
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.23 (1H, dd, J=4.5, 1.2 Hz),
7.55-7.50 (2H, m), 7.40-7.25 (2H, m), 7.45 (1H, s), 6.90 (1H, d,
J=8.1 Hz), 4.20-4.05 (6H, m), 3.49 (2H, t, J=7.2 Hz), 3.02 (2H, t,
J=7.2 Hz), 1.47 (3H, t, J=7.2 Hz), 1.47 (3H, t, J=7.2 Hz), 1.46
(3H, t, J=7.2 Hz)
Example 184
3-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-1-(3-ethoxyphenyl)propan-1-one
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.00-7.95 (2H, m), 7.60-7.50 (2H,
m), 7.43 (1H, s), 6.95-6.85 (3H, m), 4.17 (2H, q, J=7.2 Hz), 4.17
(2H, q, J=7.2 Hz), 4.09 (2H, q, J=7.2 Hz), 3.34 (2H, t, J=7.2 Hz),
3.01 (2H, t, J=7.2 Hz), 1.48 (3H, t, J=7.2 Hz), 1.48 (3H, t, J=7.2
Hz), 1.44 (3H, t, J=7.2 Hz).
Example 185
3-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-1-(4-ethoxyphenyl)propan-1-one
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.60-7.50 (4H, m), 7.44 (1H, s),
7.35 (1H, t, J=7.8 Hz), 7.09 (1H, dd, J=9.0, 2.4 Hz), 6.10 (1H, d,
J=5.4 Hz), 4.16 (2H, q, J=7.2 Hz), 4.15 (2H, q, J=7.2 Hz), 4.08
(2H, q, J=7.2 Hz), 3.38 (2H, t, J=7.2 Hz), 3.02 (2H, t, J=7.2 Hz),
1.48 (3H, t, J=7.2 Hz), 1.48 (3H, t, J=7.2 Hz), 1.40 (3H, t, J=7.2
Hz).
Example 186
Using 2 g of dimethyl
2-[2-(3,4-bis(benzyloxy)phenyl)oxazol-4-ylmethyl]malonate obtained
in Reference Example 56, 2.2 g of pale yellow oily methyl
2-[2-(3,4-bisbenzyloxyphenyl)oxazol-4-ylmethyl]-3-(3-methylpyridin-2-yl)--
3-oxopropionate was obtained in the same manner as in Example
100.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.49 (1H, dd, J=4.5, 1.2 Hz),
7.59-7.28 (15H, m), 6.94 (1H, d, J=8.4 Hz), 5.23-5.17 (5H, m), 3.69
(3H, s), 3.32-3.23 (2H, m), 2.59 (3H, s)
Example 187
Using 2.2 g of methyl
2-[2-(3,4-bisbenzyloxyphenyl)oxazol-4-ylmethyl]-3-(3-methylpyridin-2-yl)--
3-oxopropionate obtained in Example 186, 0.24 g of white powdery
3-[2-(3,4-dihydroxyphenyl)oxazol-4-ylmethyl]-1-(3-methylpyridin-2-yl)prop-
an-1-one was obtained in the same manner as in Example 136.
.sup.1H-NMR (CDCl.sub.3) .delta.: 9.46 (1H, br s), 9.32 (1H, br s),
8.54 (1H, d, J=3.0 Hz), 7.80-7.76 (2H, m), 7.54-7.49 (1H, m), 7.32
(1H, d, J=2.1 Hz), 7.23 (1H, dd, J=8.4, 2.1 Hz), 6.82 (1H, d, J=8.4
Hz), 3.47 (2H, t, J=7.5 Hz), 2.83 (2H, t, J=7.5 Hz), 2.51 (3H,
s)
Example 188
Using 0.12 g of
3-[2-(3,4-dihydroxyphenyl)oxazol-4-ylmethyl]-1-(3-methylpyridin-2-yl)prop-
an-1-one obtained in Example 187, 35 mg of white powdery
3-{2-[3,4-bis-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-yl}-1-(3-methylpyrid-
in-2-yl)propan-1-one was obtained in the same manner as in Example
111.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.50 (1H, d, J=4.5 Hz), 7.68 (1H,
dd, J=8.4, 1.8 Hz), 7.63 (1H, d, J=1.8 Hz), 7.58 (1H, d, J=8.4 Hz),
7.49 (1H, s), 7.35-7.28 (1H, m), 7.04 (1H, d, J=8.4 Hz), 4.50-4.39
(4H, m), 3.60 (2H, t, J=7.2 Hz), 3.01 (2H, t, J=7.2 Hz), 2.59 (3H,
s)
Example 189
Using 0.76 g of 4-chloromethyl-2-(3-ethoxy-4-methoxyphenyl)oxazole
obtained in Reference Example 58 and 0.5 g of
1-(2-allyloxyphenyl)ethanone obtained in Reference Example 53, 0.13
g of white powdery
1-(2-allyloxyphenyl)-3-[2-(3-ethoxy-4-methoxyphenyl)oxazol-4-yl]propan-1--
one was obtained in the same manner as in Example 177.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.70 (1H, dd, J=7.5, 2.1 Hz),
7.56 (1H, dd, J=8.4, 2.1 Hz), 7.51 (1H, d, J=2.1 Hz), 7.45-7.40
(2H, m), 7.02-6.89 (3H, m), 6.12-6.01 (1H, m), 5.42 (1H, dd, J=17,
1.5 Hz), 5.28 (1H, dd, J=17, 1.5 Hz), 4.65-4.62 (2H, m), 4.18 (2H,
q, J=6.9 Hz), 3.92 (3H, s), 3.42 (2H, t, J=7.2 Hz), 2.99 (2H, t,
J=7.2 Hz), 1.49 (3H, t, J=6.9 Hz)
Example 190
A 2 g quantity of
4-chloromethyl-2-(4-benzyloxy-3-ethoxyphenyl)oxazole obtained in
Reference Example 63 and 0.96 g of 1-(2-ethoxyphenyl)ethanone were
dissolved in 20 ml of tetrahydrofuran, and 0.47 g sodium hydride
was added thereto. After foaming, the reaction mixture was heated
and refluxed for 3 hours. After cooling, the reaction mixture was
added to ice water, and extraction was performed with ethyl
acetate. The organic layer was washed with water, dried over
magnesium sulfate, and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography
(n-hexane:ethyl acetate=3:1) to give 0.4 g of colorless powdery
3-[2-(4-benzyloxy-3-ethoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1--
one.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.70 (1H, dd, J=7.5, 1.8 Hz),
7.55-7.30 (8H, m), 6.97 (2H, t, J=7.5 Hz), 6.93 (1H, d, J=7.5 Hz),
5.19 (2H, s), 4.18 (2H, q, J=6.9 Hz), 4.13 (2H, q, J=6.9 Hz), 3.41
(2H, t, J=6.9 Hz), 2.99 (2H, t, J=6.9 Hz), 1.48 (3H, t, J=6.9 Hz),
1.47 (3H, t, J=6.9 Hz)
Example 191
Using
3-[2-(4-benzyloxy-3-ethoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)pro-
pan-1-one obtained in Example 190, colorless oily
3-[2-(3-ethoxy-4-hydroxyphenyl)oxazol-4-yl]-1-(2-ethoxy
phenyl)propan-1-one was obtained in the same manner as in Example
2.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.70 (1H, dd, J=7.5, 1.8 Hz),
7.52 (1H, dd, J=8.1, 2.1 Hz), 7.49 (1H, d, J=2.1 Hz), 7.45-7.38
(2H, m), 6.97 (1H, t, J=7.5 Hz), 6.95 (1H, d, J=7.5 Hz), 6.93 (1H,
d, J=8.1 Hz), 5.89 (1H, s), 4.20 (2H, q, J=7.2 Hz), 4.13 (2H, q,
J=7.2 Hz), 3.41 (2H, t, J=7.2 Hz), 2.98 (2H, t, J=7.2 Hz), 1.47
(3H, t, J=7.2 Hz), 1.47 (3H, t, J=7.2 Hz)
Example 192
Using
3-[2-(3-ethoxy-4-hydroxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propa-
n-1-one obtained in Example 191, colorless needle crystalline
3-[2-(3-ethoxy-4-isopropoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-
-one was obtained in the same manner as in Example 111.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.70 (1H, dd, J=7.5, 1.8 Hz),
7.54-7.51 (2H, m), 7.45-7.39 (2H, m), 6.97 (2H, br t, J=7.5 Hz),
6.93 (1H, d, J=7.5 Hz), 4.55 (1H, sept, J=6.0 Hz), 4.14 (2H, q,
J=6.9 Hz), 4.13 (2H, q, J=6.9 Hz), 3.42 (2H, t, J=7.5 Hz), 2.99
(2H, t, J=7.5 Hz), 1.47 (3H, t, J=6.9 Hz), 1.45 (3H, t, J=6.9 Hz),
1.37 (6H, d, J=6.0 Hz)
Example 193
A 2.98 g quantity of
2-(3-benzyloxy-4-methoxyphenyl)oxazole-4-carbaldehyde obtained in
Reference Example 64 and 1.72 g of 1-(2-propoxyphenyl)ethanone were
dissolved in 50 ml of pyridine. A 2.66 g quantity of potassium
carbonate was added thereto, and the mixture was heated and stirred
at 120.degree. C. for 22 hours. After cooling, the reaction mixture
was added to saturated brine, and extraction was performed with
ethyl acetate. The organic layer was washed with water and then
dried over anhydrous magnesium sulfate, and the solvent was removed
under reduced pressure. The residue was purified by silica gel
column chromatography (n-hexane:ethyl acetate=3:1) to give 1.82 g
of colorless oily
(E)-3-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-propoxyphenyl)-2--
propen-1-one.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.80 (1H, s), 7.79 (1H, d, J=15.3
Hz), 7.69-7.66 (3H, m), 7.51-7.32 (7H, m), 7.04-6.95 (3H, m), 5.21
(2H, s), 4.05 (2H, t, J=6.3 Hz), 3.94 (3H, s), 1.88 (2H, sext.,
J=6.3 Hz), 1.08 (3H, t, J=6.3 Hz)
Example 194
A 1.82 g quantity of
(E)-3-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-propoxyphenyl)-2--
propen-1-one obtained in Example 193 was dissolved in 50 ml of
methanol. A 200 mg quantity of 5% palladium-carbon powder was added
thereto, and the mixture was stirred under a hydrogen atmosphere at
room temperature for 2 hours. The catalyst was then removed by
filtration. The filtrate was diluted with 100 ml of methanol, and
500 mg of 10% palladium-carbon powder was added thereto. The
mixture was stirred under a hydrogen atmosphere at room temperature
for 3 hours. The catalyst was removed by filtration, and the
solvent was removed under reduced pressure. Diisopropyl ether was
added to the residue for crystallization to give 0.78 g of
colorless powdery
3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-propoxyphenyl)propan-1--
one.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.70 (1H, dd, J=7.5, 1.8 Hz),
7.55 (1H, d, J=2.1 Hz), 7.53 (1H, dd, J=8.1, 2.1 Hz), 7.42 (1H,
ddd, J=8.1, 7.5, 1.8 Hz), 7.40 (1H, s), 6.97 (1H, td, J=7.5, 0.9
Hz), 6.93 (1H, br d, J=8.1 Hz), 6.89 (1H, d, J=8.1 Hz), 4.02 (2H,
t, J=6.6 Hz), 3.94 (3H, s), 3.43 (2H, t, J=7.2 Hz), 2.99 (2H, t,
J=7.2 Hz), 1.88 (2H, sext., J=6.6 Hz), 1.06 (3H, t, J=6.6 Hz)
Example 195
Using 0.15 g of
3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-propoxyphenyl)propan-1--
one obtained in Example 194, 67 mg of colorless powdery
3-[2-(3-ethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-propoxyphenyl)propan-1-o-
ne was obtained in the same manner as in Example 102.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.71 (1H, dd, J=7.8, 1.8 Hz),
7.59-7.40 (4H, m), 6.97 (1H, t, J=7.8 Hz), 6.94 (1H, d, J=7.8 Hz),
6.91 (1H, d, J=7.8 Hz), 4.18 (2H, q, J=6.6 Hz), 4.02 (2H, t, J=6.6
Hz), 3.92 (3H, s), 3.43 (2H, t, J=7.2 Hz), 3.00 (2H, t, J=7.2 Hz),
1.87 (2H, sext., J=6.6 Hz), 1.49 (3H, t, J=6.6 Hz), 1.06 (3H, t,
J=6.6 Hz)
Example 196
Using 0.15 g of
3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-propoxyphenyl)propan-1--
one obtained in Example 194, 67 mg of colorless oily
3-[2-(3-cyclopentyloxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-propoxyphenyl)pr-
opan-1-one was obtained in the same manner as in Example 102.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.71 (1H, dd, J=7.5, 1.8 Hz),
7.55 (1H, dd, J=8.4, 1.8 Hz), 7.51 (1H, d, J=1.8 Hz), 7.42 (1H, br
t, J=7.5 Hz), 7.39 (1H, s), 6.97 (1H, t, J=7.5 Hz), 6.93 (1H, d,
J=7.5 Hz), 6.89 (1H, d, J=8.4 Hz), 4.90-4.84 (1H, m), 4.02 (2H, t,
J=6.6 Hz), 3.88 (3H, s), 3.43 (2H, t, J=7.2 Hz), 2.99 (2H, t, J=7.2
Hz), 2.03-1.60 (10H, m), 1.05 (3H, t, J=7.2 Hz)
Example 197
Using
3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-propoxyphenyl)pro-
pan-1-one obtained in Example 194, colorless oily
3-[2-(3-isopropoxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-propoxy
phenyl)propan-1-one was obtained in the same manner as in Example
102.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.71 (1H, dd, J=7.8, 1.8 Hz),
7.57 (1H, dd, J=8.4, 2.1 Hz), 7.54 (1H, d, J=2.1 Hz), 7.42 (1H,
ddd, J=8.4, 7.2, 1.8 Hz), 7.39 (1H, s), 6.97 (1H, br t, J=7.2 Hz),
6.96 (1H, br d, J=8.4 Hz), 6.91 (1H, d, J=8.4 Hz), 4.65 (1H, sept.,
J=6.0 Hz), 4.02 (2H, t, J=7.2 Hz), 3.90 (3H, s), 3.43 (2H, t, J=7.2
Hz), 2.99 (2H, t, J=7.2 Hz), 1.87 (2H, sext., J=7.2 Hz), 1.40 (6H,
d, J=6.0 Hz), 1.06 (3H, t, J=7.2 Hz)
Example 198
Using
3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-propoxyphenyl)pro-
pan-1-one obtained in Example 194, colorless powdery
3-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-propoxypheny-
l)propan-1-one was obtained in the same manner as in Example
102.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.70 (1H, dd, J=7.5, 1.8 Hz),
7.57 (1H, dd, J=8.4, 1.8 Hz), 7.50 (1H, d, J=1.8 Hz), 7.45-7.39
(2H, m), 6.97 (1H, br t, J=7.5 Hz), 6.93 (1H, br d, J=7.5 Hz), 6.91
(1H, br d, J=8.4 Hz), 4.02 (2H, t, J=6.6 Hz), 3.92 (2H, d, J=7.2
Hz), 3.92 (3H, s), 3.43 (2H, t, J=7.2 Hz), 2.99 (2H, t, J=7.2 Hz),
1.87 (2H, sext., J=6.6 Hz), 1.41-1.32 (1H, m), 1.06 (3H, t, J=6.6
Hz), 0.69-0.63 (2H, m), 0.40-0.35 (2H, m)
Example 199
Using
3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-propoxyphenyl)pro-
pan-1-one obtained in Example 194, colorless needle crystalline
3-[2-(3-(3-butenyloxy)-4-methoxyphenyl)oxazol-4-yl]-1-(2-propoxyphenyl)pr-
opan-1-one was obtained in the same manner as in Example 102.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.71 (1H, dd, J=7.7, 1.5 Hz),
7.58 (1H, dd, J=8.5, 2.0 Hz), 7.52 (1H, d, J=2.0 Hz), 7.42 (1H,
ddd, J=7.7, 7.5, 1.8 Hz), 7.40 (1H, s), 6.97 (1H, ddd, J=7.7, 7.5,
0.9 Hz), 6.93 (1H, br d, J=7.7 Hz), 6.91 (1H, d, J=8.5 Hz), 5.92
(1H, ddt, J=17.3, 10.3, 6.8 Hz), 5.19 (1H, ddd, J=17.3, 3.3, 1.5
Hz), 5.11 (1H, ddd, J=10.3. 3.3, 0.6 Hz), 4.14 (2H, t, J=7.2 Hz),
4.02 (2H, t, J=7.2 Hz), 3.91 (3H, s), 3.43 (2H, t, J=7.2 Hz), 2.99
(2H, t, J=7.2 Hz), 2.63 (2H, br q, J=6.9 Hz), 1.87 (2H, sext.,
J=7.2 Hz), 1.06 (3H, t, J=7.2 Hz)
Example 200
Using
3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-propoxyphenyl)pro-
pan-1-one obtained in Example 194, colorless needle crystalline
3-[2-(3-allyloxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-propoxyphenyl)propan-1-
-one was obtained in the same manner as in Example 102.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.71 (1H, dd, J=7.7, 1.8 Hz),
7.59 (1H, dd, J=8.5, 1.8 Hz), 7.52 (1H, d, J=1.8 Hz), 7.42 (1H,
ddd, J=8.3, 7.7, 1.8 Hz), 7.40 (1H, s), 6.97 (1H, td, J=7.7, 1.1
Hz), 6.93 (1H, br d, J=8.3 Hz), 6.91 (1H, d, J=8.5 Hz), 6.12 (1H,
ddt, J=17.3, 10.5, 5.5 Hz), 5.44 (1H, ddd, J=17.3, 3.0, 1.5 Hz),
5.31 (1H, ddd, J=10.5. 3.0, 1.5 Hz), 4.67 (2H, dt, J=5.5, 1.5 Hz),
4.02 (2H, t, J=6.3 Hz), 3.92 (3H, s), 3.43 (2H, t, J=7.2 Hz), 2.99
(2H, t, J=7.2 Hz), 1.87 (2H, sext., J=6.3 Hz), 1.06 (3H, t, J=6.3
Hz)
Example 201
Using 0.1 g of
3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-propoxyphenyl)propan-1--
one obtained in Example 194, 67 mg of colorless powdery
3-[2-(3-cyclobutylmethoxy-4-methoxy
phenyl)oxazol-4-yl]-1-(2-propoxyphenyl)propan-1-one was obtained in
the same manner as in Example 111.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.71 (1H, dd, J=7.8, 1.8 Hz),
7.56 (1H, dd, J=7.8, 1.8 Hz), 7.52 (1H, d, J=1.8 Hz), 7.45-7.40
(2H, m), 6.98 (1H, t, J=7.8 Hz), 6.94 (1H, d, J=7.8 Hz), 6.90 (1H,
d, J=7.8 Hz), 4.07 (2H, d, J=6.9 Hz), 4.02 (2H, t, J=6.6 Hz), 3.90
(3H, s), 3.44 (2H, t, J=7.2 Hz), 3.00 (2H, t, J=7.2 Hz), 2.86 (1H,
quint, J=7.2 Hz), 2.21-2.16 (2H, m), 1.96-1.84 (6H, m), 1.06 (3H,
t, J=7.5 Hz)
Example 202
Using
2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazole-4-carbaldehyde
obtained in Reference Example 65, pale yellow oily
(E)-3-{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-yl}-1-(2-pro-
poxyphenyl)-2-propen-1-one was obtained in the same manner as in
Example 193.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.83 (1H, d, J=15.0 Hz), 7.81
(1H, s), 7.76 (1H, dd, J=8.4, 2.1 Hz), 7.69 (1H, dd, J=7.8, 1.8
Hz), 7.69 (1H, d, J=2.1 Hz), 7.50 (1H, d, J=15.0 Hz), 7.45 (1H,
ddd, J=8.4, 7.8, 1.8 Hz), 7.01 (1H, br t, J=8.4 Hz), 6.99 (1H, d,
J=8.4 Hz), 6.98 (1H, br d, J=7.8 Hz), 4.46 (2H, q, J=8.4 Hz), 4.06
(2H, t, J=6.3 Hz), 3.94 (3H, s), 1.90 (2H, sext., J=6.3 Hz), 1.09
(3H, t, J=6.3 Hz)
Example 203
Using
(E)-3-{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-yl}-1--
(2-propoxyphenyl)-2-propen-1-one obtained in Example 202, colorless
powdery
3-{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-yl}-1-(2-
-propoxyphenyl)propan-1-one was obtained in the same manner as in
Example 194.
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 7.83 (1H, s), 7.62 (1H, dd,
J=7.8, 1.8 Hz), 7.57 (1H, dd, J=7.8, 1.5 Hz), 7.55 (1H, d, J=1.5
Hz), 7.51 (1H, br t, J=7.8 Hz), 7.17 (1H, d, J=7.8 Hz), 7.15 (1H,
d, J=7.8 Hz), 7.01 (1H, t, J=7.8 Hz), 4.80 (2H, q, J=9.0 Hz), 4.06
(2H, t, J=6.6 Hz), 3.86 (3H, s), 3.33 (2H, t, J=7.2 Hz), 2.84 (2H,
t, J=7.2 Hz), 1.79 (2H, sext., J=6.6 Hz), 0.99 (3H, t, J=6.6
Hz)
Example 204
Using 2-(3,4-diethoxyphenyl)oxazole-4-carbaldehyde obtained in
Reference Example 66, pale yellow powdery
(E)-3-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-1-(2-propoxyphenyl)-2-propen-1--
one was obtained in the same manner as in Example 193.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.81 (1H, d, J=15.0 Hz), 7.79
(1H, br d, J=7.5 Hz), 7.68 (1H, dd, J=7.8, 1.8 Hz), 7.62 (1H, d,
J=1.8 Hz), 7.59 (1H, br s), 7.49 (1H, d, J=15.0 Hz), 7.44 (1H, br
t, J=7.5 Hz), 7.01 (1H, br t, J=7.5 Hz), 6.97 (1H, br d, J=7.5 Hz),
6.93 (1H, d, J=7.8 Hz), 4.18 (2H, q, J=6.9 Hz), 4.16 (2H, q, J=6.9
Hz), 4.05 (2H, t, J=6.3 Hz), 1.89 (1H, br sext., J=6.9 Hz), 1.50
(3H, t, J=6.9 Hz), 1.49 (3H, t, J=6.9 Hz), 1.09 (3H, t, J=7.2
Hz)
Example 205
Using
(E)-3-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-1-(2-propoxyphenyl)-2-pro-
pen-1-one obtained in Example 204, colorless powdery
3-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-1-(2-propoxyphenyl)propan-1-one
was obtained in the same manner as in Example 194.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.60 (1H, dd, J=7.8, 1.8 Hz),
7.54 (1H, dd, J=8.4, 2.1 Hz), 7.52 (1H, d, J=2.1 Hz), 7.42 (1H,
ddd, J=7.8, 7.2, 1.8 Hz), 7.39 (1H, s), 6.97 (1H, td, J=7.8, 1.2
Hz), 6.93 (1H, br d, J=7.2 Hz), 6.90 (1H, d, J=8.4 Hz), 4.17 (2H,
q, J=6.9 Hz), 4.14 (2H, q, J=6.9 Hz), 4.02 (2H, t, J=6.6 Hz), 3.43
(2H, t, J=7.2 Hz), 2.99 (2H, t, J=7.2 Hz), 1.87 (2H, sept., J=6.6
Hz), 1.48 (6H, t, J=6.9 Hz), 1.05 (3H, t, J=6.6 Hz)
Example 206
Using 2-(3-benzyloxy-4-methoxyphenyl)oxazole-4-carbaldehyde
obtained in Reference Example 64, pale yellow powdery
(E)-3-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-isopropoxyphenyl)-
-2-propen-1-one was obtained in the same manner as in Example
193.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.79 (1H, s), 7.79 (1H, d, J=15.3
Hz), 7.69-7.65 (3H, m), 7.50-7.32 (7H, m), 7.03-6.95 (3H, m), 5.21
(2H, s), 4.66 (1H, sept, J=6.0 Hz), 3.94 (3H, s), 1.41 (6H, d,
J=6.0 Hz)
Example 207
Using
(E)-3-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-isopropoxyp-
henyl)-2-propen-1-one obtained in Example 206, colorless powdery
3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-isopropoxyphenyl)propan-
-1-one was obtained in the same manner as in Example 194.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.67 (1H, dd, J=7.5, 1.8 Hz),
7.55 (1H, br s), 7.54 (1H, dd, J=7.5, 1.8 Hz), 7.40 (1H, td, J=7.5,
1.8 Hz), 7.40 (1H, s), 6.95 (1H, br t, J=7.5 Hz), 6.93 (1H, br d,
J=7.5 Hz), 6.89 (1H, d, J=7.5 Hz), 5.64 (1H, s), 4.68 (1H, sept.,
J=6.0 Hz), 3.94 (3H, s), 3.40 (2H, t, J=7.2 Hz), 2.98 (2H, t, J=7.2
Hz), 1.40 (6H, d, J=6.0 Hz)
The above compound was also obtained by the following method. A 10
g quantity of 2-(3-benzyloxy-4-methoxyphenyl-4-chloromethyloxazole
obtained in Reference Example 5 and 5.4 g of
1-(2-isopropoxyphenyl)ethanone were dissolved in 100 ml of
tetrahydrofuran, and 2.42 g of sodium hydride was added thereto.
After foaming, the reaction mixture was heated and refluxed for 3
hours. After cooling, the reaction mixture was added to ice water,
and extraction was performed with ethyl acetate. The organic layer
was washed with water, dried over magnesium sulfate, and then
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (n-hexane:ethyl acetate=3:1) to
give 4.30 g of pale yellow oily
3-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-isopropoxyphenyl)prop-
an-1-one. Subsequently, 1.84 g of the obtained
3-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-isopropoxyphenyl)prop-
an-1-one was dissolved in 100 ml of methanol. An 800 mg quantity of
10% palladium-carbon powder was added thereto. The mixture was
stirred under a hydrogen atmosphere at room temperature for 1 hour.
The catalyst was removed by filtration, and the solvent was
removed. The residue was then recrystallized from
acetone/diisopropyl ether to give 1.15 g of
3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-isopropoxyphenyl)propan-
-1-one.
Example 208
Using 0.15 g of
3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-isopropoxyphenyl)propan-
-1-one obtained in Example 207, 0.12 g of pale yellow oily
3-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-isopropoxyph-
enyl)propan-1-one was obtained in the same manner as in Example
102.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.67 (1H, dd, J=7.8, 1.8 Hz),
7.57 (1H, dd, J=8.4, 2.1 Hz), 7.50 (1H, d, J=2.1 Hz), 7.41 (1H, td,
J=7.8, 1.8 Hz), 7.39 (1H, s), 6.95 (1H, br t, J=7.8 Hz), 6.93 (1H,
br d, J=7.8 Hz), 6.91 (1H, d, J=8.4 Hz), 4.68 (1H, sept., J=6.0
Hz), 3.92 (2H, d, J=6.9 Hz), 3.92 (3H, s), 3.41 (2H, t, J=7.2 Hz),
2.98 (2H, t, J=7.2 Hz), 1.40 (6H, d, J=6.0 Hz), 1.46-1.32 (1H, m),
0.69-0.62 (2H, m), 0.40-0.35 (2H, m)
Example 209
Using 0.15 g of
3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-isopropoxyphenyl)propan-
-1-one obtained in Example 207, 42 mg of colorless powdery
3-[2-(3-ethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-isopropoxyphenyl)propan--
1-one was obtained in the same manner as in Example 102.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.68 (1H, dd, J=7.7, 1.8 Hz),
7.57 (1H, dd, J=8.5, 2.0 Hz), 7.52 (1H, d, J=2.0 Hz), 7.41 (1H, td,
J=7.7, 1.8 Hz), 7.40 (1H, s), 6.95 (1H, br t, J=7.7 Hz), 6.94 (1H,
br d, J=7.7 Hz), 6.91 (1H, d, J=8.5 Hz), 4.69 (1H, sept., J=6.0
Hz), 4.18 (2H, q, J=6.9 Hz), 3.92 (3H, s), 3.41 (2H, t, J=6.9 Hz),
2.99 (2H, t, J=6.9 Hz), 1.49 (3H, t, J=6.9 Hz), 1.40 (6H, d, J=6.0
Hz)
Example 210
Using
3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-isopropoxyphenyl)-
propan-1-one obtained in Example 207, pale yellow oily
3-[2-(3-isopropoxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-isopropoxyphenyl)pro-
pan-1-one was obtained in the same manner as in Example 102.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.68 (1H, dd, J=7.5, 1.8 Hz),
7.57 (1H, dd, J=7.5, 1.8 Hz), 7.54 (1H, d, J=1.8 Hz), 7.44-7.38
(2H, m), 6.95 (1H, br t, J=7.5 Hz), 6.94 (1H, d, J=7.5 Hz), 6.91
(1H, d, J=7.5 Hz), 4.67 (2H, sept., J=6.0 Hz), 3.90 (3H, s), 3.40
(2H, t, J=7.2 Hz), 2.98 (2H, t, J=7.2 Hz), 1.40 (12H, d, J=6.0
Hz)
Example 211
Using
3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-isopropoxyphenyl)-
propan-1-one obtained in Example 207, colorless oily
3-[2-(3-allyloxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-isopropoxyphenyl)propa-
n-1-one was obtained in the same manner as in Example 102.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.68 (1H, dd, J=7.7, 1.8 Hz),
7.58 (1H, dd, J=8.3, 1.8 Hz), 7.53 (1H, d, J=1.8 Hz), 7.41 (1H,
ddd, J=7.9, 7.7, 1.8 Hz), 7.40 (1H, s), 6.98 (1H, td, J=7.9, 1.8
Hz), 6.94 (1H, br d, J=7.7 Hz), 6.92 (1H, d, J=8.3 Hz), 6.12 (1H,
ddt, J=17.3, 10.5, 5.3 Hz), 5.44 (1H, ddd, J=17.3, 3.0, 1.7 Hz),
5.31 (1H, ddd, J=10.5. 3.0, 1.5 Hz), 4.75-4.60 (3H, m), 3.92 (3H,
s), 3.41 (2H, t, J=7.2 Hz), 2.99 (2H, t, J=7.2 Hz), 1.40 (6H, d,
J=6.0 Hz).
Example 212
Using
3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-isopropoxyphenyl)-
propan-1-one obtained in Example 207, colorless needle crystalline
3-[2-(3-(3-butenyloxy)-4-methoxyphenyl)oxazol-4-yl]-1-(2-isopropoxyphenyl-
)propan-1-one was obtained in the same manner as in Example
102.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.67 (1H, dd, J=7.9, 1.8 Hz),
7.57 (1H, dd, J=8.5, 2.0 Hz), 7.53 (1H, d, J=2.0 Hz), 7.40 (1H,
ddd, J=7.9, 7.5, 1.8 Hz), 7.40 (1H, s), 6.95 (1H, br t, J=7.5 Hz),
6.93 (1H, br d, J=7.5 Hz), 6.91 (1H, d, J=8.5 Hz), 5.92 (1H, ddt,
J=17.1, 10.3, 6.8 Hz), 5.19 (1H, ddd, J=17.3, 3.3, 1.5 Hz), 3.51
(1H, ddd, J=10.3. 3.3, 1.3 Hz), 4.68 (1H, sept., J=6.0 Hz), 4.14
(2H, t, J=7.2 Hz), 3.91 (3H, s), 3.41 (2H, t, J=7.2 Hz), 3.01 (2H,
t, J=7.2 Hz), 2.63 (2H, br q, J=7.2 Hz), 1.40 (6H, d, J=6.0 Hz)
Example 213
Using 0.15 g of
3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-isopropoxyphenyl)propan-
-1-one obtained in Example 207, 40 mg of colorless powdery
1-(2-isopropoxyphenyl)-3-{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]ox-
azol-4-yl}propan-1-one was obtained in the same manner as in
Example 111.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.70-7.60 (2H, m), 7.44-7.38 (2H,
m), 6.98-6.91 (4H, m), 4.69 (1H, sept., J=6.0 Hz), 4.48-4.41 (2H,
m), 3.93 (3H, s), 3.42 (2H, t, J=7.2 Hz), 3.00 (2H, t, J=7.2 Hz),
1.41 (6H, d, J=6.0 Hz)
Example 214
Using
3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-isopropoxyphenyl)-
propan-1-one obtained in Example 207, colorless powdery
3-[2-(3-cyclobutylmethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-isopropoxyphe-
nyl)propan-1-one was obtained in the same manner as in Example
111.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.68 (1H, dd, J=8.4, 1.8 Hz),
7.56 (1H, dd, J=8.4, 1.8 Hz), 7.52 (1H, d, J=1.8 Hz), 7.44-7.38
(2H, m), 6.95 (1H, br t, J=8.4 Hz), 6.94 (1H, br d, J=8.4 Hz), 6.90
(1H, d, J=8.4 Hz), 4.69 (1H, sept., J=6.0 Hz), 4.07 (2H, d, J=6.9
Hz), 3.90 (3H, s), 3.41 (2H, t, J=7.2 Hz), 2.99 (2H, t, J=7.2 Hz),
2.86 (1H, quint, J=7.2 Hz), 2.22-2.14 (2H, m), 1.99-1.84 (4H, m),
1.40 (6H, d, J=6.0 Hz)
Example 215
Using 2-(3,4-diethoxyphenyl)oxazole-4-carbaldehyde obtained in
Reference Example 66, yellow oily
(E)-3-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-1-(2-isopropoxyphenyl)-2-propen-
-1-one was obtained in the same manner as in Example 193.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.81 (1H, d, J=15.3 Hz), 7.79
(1H, br s), 7.69-7.53 (3H, m), 7.46 (1H, d, J=15.3 Hz), 7.43 (1H,
td, J=7.8, 1.2 Hz), 7.00 (1H, br t, J=7.8 Hz), 6.93 (1H, br d,
J=7.8 Hz), 6.91 (1H, br d, J=7.8 Hz), 4.67 (1H, sept, J=6.0 Hz),
4.22-4.11 (4H, m), 1.52-1.45 (6H, m), 1.41 (6H, d, J=6.0 Hz)
Example 216
Using
(E)-3-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-1-(2-isopropoxyphenyl)-2--
propen-1-one obtained in Example 215, pale yellow oily
3-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-1-(2-isopropoxy
phenyl)propan-1-one was obtained in the same manner as in Example
194.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.67 (1H, dd, J=7.5, 1.5 Hz),
7.60-7.38 (4H, m), 6.97-6.89 (3H, m), 4.68 (1H, sept, J=6.0 Hz),
4.21-4.10 (4H, m), 3.41 (2H, t, J=7.2 Hz), 2.98 (2H, t, J=7.2 Hz),
1.48 (6H, br t, J=7.2 Hz), 1.40 (6H, d, J=6.0 Hz)
Example 217
Using 2-(3,4-diethoxyphenyl)oxazole-4-carbaldehyde obtained in
Reference Example 66, colorless powdery
(E)-3-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-1-o-tolyl-2-propen-1-one
was obtained in the same manner as in Example 193.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.81 (1H, s), 7.64-7.28 (8H, m),
6.93 (1H, d, J=8.1 Hz), 4.20 (2H, q, J=6.9 Hz), 4.16 (2H, q, J=6.9
Hz), 2.47 (3H, s), 1.50 (3H, t, J=6.9 Hz), 1.49 (3H, t, J=6.9
Hz)
Example 218
Using
(E)-3-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-1-o-tolyl-2-propen-1-one
obtained in Example 217, colorless needle crystalline
3-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-1-o-tolyl propan-1-one was
obtained in the same manner as in Example 194.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.68 (1H, dd, J=7.5, 1.8 Hz),
7.55 (1H, dd, J=8.1, 1.8 Hz), 7.51 (1H, d, J=1.8 Hz), 7.43 (1H, br
s), 7.36 (1H, td, J=7.5, 1.5 Hz), 7.27-7.22 (2H, m), 6.90 (1H, d,
J=8.1 Hz), 4.17 (2H, q, J=6.9 Hz), 4.14 (2H, q, J=6.9 Hz), 3.32
(2H, t, J=7.2 Hz), 3.00 (2H, t, J=7.2 Hz), 2.49 (3H, s), 1.48 (6H,
t, J=6.9 Hz)
Example 219
Using 2-(3-benzyloxy-4-methoxyphenyl)oxazole-4-carbaldehyde
obtained in Reference Example 64, pale yellow powdery
(E)-3-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-yl]-1-o-tolyl-2-propen-1-o-
ne was obtained in the same manner as in Example 193.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.81 (1H, s), 7.69-7.26 (13H, m),
6.96 (1H, d, J=9.0 Hz), 5.23 (2H, s), 3.94 (3H, s), 2.47 (3H,
s)
Example 220
Using
(E)-3-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-yl]-1-o-tolyl-2-prop-
en-1-one obtained in Example 219, colorless powdery
3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-o-tolyl propan-1-one
was obtained in the same manner as in Example 194.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.67 (1H, dd, J=7.2, 1.8 Hz),
7.56 (1H, d, J=1.8 Hz), 7.53 (1H, dd, J=8.1, 1.8 Hz), 7.43 (1H, s),
7.35 (1H, td, J=7.2, 1.8 Hz), 7.26-7.22 (2H, m), 6.89 (1H, d, J=8.1
Hz), 5.69 (1H, s), 3.94 (3H, s), 3.31 (2H, t, J=7.2 Hz), 3.00 (2H,
t, J=7.2 Hz), 2.49 (3H, s)
Example 221
A 0.15 g quantity of
3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-o-tolylpropan-1-one
obtained in Example 220 was dissolved in 10 ml of isopropyl
alcohol. An 86 .mu.l quantity of (bromomethyl)cyclopropane and 200
.mu.l of 1,8-diazabicyclo[5,4,0]undec-7-ene were added thereto, and
the mixture was heated and refluxed for 24 hours. Water was added
to the reaction mixture, and extraction was then performed with
ethyl acetate. The organic layer was washed with saturated brine,
dried over anhydrous magnesium sulfate, and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (n-hexane:ethyl acetate=3:1), and recrystallized
from acetone/diisopropyl ether/n-hexane to give 71 mg of colorless
needle crystalline
3-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-yl]-1-o-tolylpropan-1-
-one.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.68 (1H, dd, J=7.5, 1.5 Hz),
7.57 (1H, dd, J=8.1, 2.1 Hz), 7.49 (1H, d, J=2.1 Hz), 7.43 (1H, t,
J=0.9 Hz), 7.36 (1H, td, J=7.5, 1.5 Hz), 7.25-7.22 (2H, m), 6.91
(1H, d, J=8.1 Hz), 3.93 (2H, d, J=6.9 Hz), 3.92 (3H, s), 3.32 (2H,
t, J=7.2 Hz), 3.00 (2H, t, J=7.2 Hz), 2.49 (3H, s), 1.41-1.32 (1H,
m), 0.69-0.63 (2H, m), 0.40-0.35 (2H, m)
Example 222
Using 2-(3-isopropoxy-4-methoxyphenyl)oxazole-4-carbaldehyde
obtained in Reference Example 69, yellow powdery
(E)-3-[2-(3-isopropoxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-benzyloxyphenyl)-
-2-propen-1-one was obtained in the same manner as in Example
193.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.76 (1H, s), 7.69-6.92 (14H, m),
5.20 (2H, s), 4.63 (1H, sept., J=6.0 Hz), 1.38 (6H, d, J=6.0
Hz)
Example 223
Using
(E)-3-[2-(3-isopropoxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-benzyloxyp-
henyl)-2-propen-1-one obtained in Example 222, colorless plate
crystalline
1-(2-hydroxyphenyl)-3-[2-(3-isopropoxy-4-methoxyphenyl)oxazol-4-yl]propan-
-1-one was obtained in the same manner as in Example 194.
.sup.1H-NMR (CDCl.sub.3) .delta.: 12.25 (1H, s), 7.82 (1H, dd,
J=8.4, 1.5 Hz), 7.58 (1H, dd, J=8.4, 1.8 Hz), 7.54 (1H, d, J=1.8
Hz), 7.46 (1H, ddd, J=8.4, 7.2, 1.5 Hz), 7.45 (1H, s), 6.98 (1H,
dd, J=8.4, 1.2 Hz), 6.92 (1H, d, J=8.4 Hz), 6.89 (1H, ddd, J=8.4,
7.2, 1.2 Hz), 4.65 (1H, sept., J=6.0 Hz), 3.90 (3H, s), 3.44 (2H,
t, J=7.5 Hz), 3.03 (2H, t, J=7.5 Hz), 1.40 (6H, d, J=6.0 Hz)
Example 224
A 67 mg quantity of
1-(2-hydroxyphenyl)-3-[2-(3-isopropoxy-4-methoxyphenyl)oxazol-4-yl]propan-
-1-one obtained in Example 223 was dissolved in 5 ml of
dimethylformamide. A 31 .mu.l quantity of allyl bromide and 73 mg
of potassium carbonate were added thereto, and the mixture was
stirred at room temperature overnight. A 50 .mu.l quantity of allyl
bromide was further added thereto, and the mixture was stirred at
50.degree. C. for 8 hours, and at room temperature overnight. The
reaction mixture was added to water, and extraction was then
performed with ethyl acetate. The organic layer was washed with
saturated brine, dried over anhydrous magnesium sulfate, and the
solvent was removed under reduced pressure. The residue was
purified by silica gel column chromatography (n-hexane:ethyl
acetate 3:1), and crystallized from n-hexane to give 33 mg of
colorless powdery
1-(2-allyloxyphenyl)-3-[2-(3-isopropoxy-4-methoxyphenyl)oxazol-4-yl]propa-
n-1-one.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.70 (1H, dd, J=7.8, 1.8 Hz),
7.57 (1H, dd, J=8.4, 2.1 Hz), 7.54 (1H, d, J=2.1 Hz), 7.44 (1H,
ddd, J=7.8, 7.5, 1.8 Hz), 7.40 (1H, br s), 6.99 (1H, td, J=7.8, 1.2
Hz), 6.94 (1H, br d, J=7.5 Hz), 6.91 (1H, d, J=8.4 Hz), 6.08 (1H,
ddt, J=17.1, 10.5, 5.4 Hz), 5.42 (1H, ddd, J=17.1, 3.0, 1.5 Hz),
5.29 (1H, ddd, J=10.5, 2.7, 1.5 Hz), 4.69-4.61 (3H, m), 3.89 (3H,
s), 3.42 (2H, t, J=7.2 Hz), 2.99 (2H, t, J=7.2 Hz), 1.39 (6H, d,
J=6.3 Hz)
Example 225
Using 0.3 g of
3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-o-tolylpropan-1-one
obtained in Example 220, 0.15 g of white powdery
3-[2-(3-ethoxy-4-methoxyphenyl)oxazol-4-yl]-1-o-tolylpropan-1-one
was obtained in the same manner as in Example 3.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.68 (1H, m), 7.57 (1H, dd,
J=8.1, 2.1 Hz), 7.51 (1H, d, J=2.1 Hz), 7.44 (1H, d, J=0.9 Hz),
7.36 (1H, m), 7.30-7.20 (3H, m), 6.91 (1H, d, J=8.4 Hz), 4.18 (2H,
q, J=6.9 Hz), 3.92 (3H, s), 3.35-3.25 (2H, m), 3.05-2.95 (2H, m),
2.50 (3H, s), 1.50 (3H, t, J=6.9 Hz)
Example 226
Using 0.3 g of
3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-o-tolylpropan-1-one
obtained in Example 220, 0.1 g of white powdery
3-[2-(3-allyloxy-4-methoxyphenyl)oxazol-4-yl]-1-o-tolylpropan-1-one
was obtained in the same manner as in Example 3.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.68 (1H, m), 7.59 (1H, dd,
J=8.4, 2.1 Hz), 7.52 (1H, d, J=2.1 Hz), 7.43 (1H, s), 7.38 (1H, m),
7.35-7.25 (2H, m), 6.92 (1H, d, J=8.4 Hz), 6.13 (1H, ddd, J=17.1,
10.5, 5.4 Hz), 5.44 (1H, ddd, J=17.1, 2.7, 1.5 Hz), 5.31 (1H, ddd,
J=10.5, 2.7, 1.5 Hz), 4.68 (1H, dt, J=5.4, 1.5 Hz), 3.92 (3H, s),
3.32 (2H, t, J=7.2 Hz), 3.00 (2H, t, J=7.2 Hz), 2.50 (3H, s)
Example 227
Using 0.2 g of
3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-o-tolylpropan-1-one
obtained in Example 220, 0.1 g of pale yellow oily
3-[2-(3-isopropoxy-4-methoxyphenyl)oxazol-4-yl]-1-o-tolylpropan-1-one
was obtained in the same manner as in Example 3.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.69 (1H, m), 7.60-7.50 (2H, m),
7.50-7.30 (3H, m), 7.24 (1H, m), 6.91 (1H, dd, J=5.1, 3.0 Hz), 4.65
(1H, m), 3.90 (3H, s), 3.35-3.25 (2H, m), 3.05-2.95 (2H, m), 2.49
(3H, s), 1.40 (6H, d, J=6.0 Hz)
Example 228
A 65 mg quantity of sodium hydride was suspended in 5 ml of
tetrahydrofuran. A 0.27 g quantity of 1-(2-ethoxyphenyl)ethanone
and 0.3 g of 2-(3-benzyloxy-4-difluoro
methoxyphenyl)-4-chloromethyloxazole obtained in Reference Example
44 was successively added thereto with ice-cooling and stirring,
and the mixture was stirred for 3 hours with heating and refluxing.
An aqueous saturated ammonium chloride solution was added to the
reaction mixture with ice-cooling and stirring. After stirring for
15 minutes, water was added thereto, and extraction was performed
with ethyl acetate. The mixture was dried over anhydrous magnesium
sulfate, and the solvent was removed. The obtained residue was
purified by silica gel column chromatography (n-hexane:ethyl
acetate=4:1) to give 75 mg of colorless oily
3-[2-(3-benzyloxy-4-difluoromethoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)-
propan-1-one.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.72-7.69 (2H, m), 7.59 (1H, dd,
J=8.1, 1.8 Hz), 7.47-7.32 (7H, m), 7.00-6.92 (3H, m), 6.61 (1H, t,
J=74.7 Hz), 5.20 (2H, s), 4.15 (2H, q, J=7.2 Hz), 3.43 (2H, t,
J=7.2 Hz), 3.00 (2H, t, J=7.2 Hz), 1.48 (3H, t, J=7.2 Hz)
Example 229
A 75 mg quantity of
3-[2-(3-benzyloxy-4-difluoromethoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)-
propan-1-one obtained in Example 228 was dissolved in 1 ml of
ethanol. A 7 mg quantity of 10% palladium-carbon powder was added
thereto, and the mixture was stirred under a hydrogen atmosphere at
room temperature for 45 minutes. The catalyst was removed by
filtration, the filtrate was concentrated, and the obtained residue
was purified by silica gel column chromatography
(dichloromethane:ethanol=100:1) to give 32 mg of white powdery
3-[2-(4-difluoromethoxy-3-hydroxyphenyl)oxazol-4-yl]-1-(2-ethoxyp-
henyl)propan-1-one.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.70 (1H, dd, J=7.5, 1.8 Hz),
7.65 (1H, d, J=1.8 Hz), 7.56-7.43 (3H, m), 7.16 (1H, d, J=6.0 Hz),
6.98-6.92 (2H, m), 6.57 (1H, t, J=74.7 Hz), 5.57 (1H, s), 4.13 (2H,
q, J=7.2 Hz), 3.42 (2H, t, J=7.2 Hz), 3.00 (2H, t, J=7.2 Hz), 1.48
(3H, t, J=7.2 Hz)
Example 230
A 30 mg quantity of
3-[2-(4-difluoromethoxy-3-hydroxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)pr-
opan-1-one obtained in Example 229 was dissolved in 0.5 ml of
dimethylformamide. An 18 mg quantity of 2-bromopropane and 30 mg of
potassium carbonate were added thereto, and the mixture was stirred
at room temperature overnight. Water was added to the reaction
mixture, and extraction was performed with ethyl acetate. Drying
was performed with anhydrous magnesium sulfate, and the solvent was
removed. The obtained residue was purified by silica gel column
chromatography (n-hexane:ethyl acetate=4:1) to give 23 mg of white
powdery
3-[2-(4-difluoromethoxy-3-isopropoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl-
)propan-1-one.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.70 (1H, dd, J=7.8, 1.8 Hz),
7.61 (1H, d, J=1.8 Hz), 7.55 (1H, dd, J=8.4, 1.8 Hz), 7.50-7.38
(2H, m), 7.19 (1H, d, J=8.1 Hz), 7.00-6.70 (2H, m), 6.60 (1H, t,
J=74.7 Hz), 4.72-4.64 (1H, m), 4.13 (2H, q, J=7.2 Hz), 3.42 (2H, t,
J=7.2 Hz), 3.00 (2H, t, J=7.2 Hz), 1.48 (3H, t, J=7.2 Hz), 1.39
(6H, d, J=6.0 Hz)
Example 231
Using 2-(3-benzyloxy-4-methoxyphenyl)-4-chloromethyl oxazole
obtained in Reference Example 5 and 1-(2-methoxymethoxy
phenyl)ethanone obtained in Reference Example 70, yellow oily
3-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-methoxymethoxy
phenyl)propan-1-one was obtained in the same manner as in Example
190.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.66 (1H, dd, J=7.8, 1.8 Hz),
7.59 (1H, dd, J=7.8, 1.8 Hz), 7.51 (1H, br s), 7.49-7.27 (7H, m),
7.17 (1H, br d, J=7.8 Hz), 7.04 (1H, td, J=7.5, 1.2 Hz), 6.93 (1H,
br d, J=7.8 Hz), 5.25 (2H, s), 5.19 (2H, s), 3.92 (3H, s), 3.48
(3H, s), 3.39 (2H, t, J=7.2 Hz), 3.00 (2H, t, J=7.2 Hz)
Example 232
Using
3-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-methoxymethoxyp-
henyl)propan-1-one obtained in Example 231,
3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-methoxymethoxy
phenyl)propan-1-one was obtained in the same manner as in Example
194.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.66 (1H, dd, J=7.8, 1.8 Hz),
7.55 (1H, d, J=2.1 Hz), 7.53 (1H, dd, J=8.1, 2.1 Hz), 7.41 (1H, s),
7.41 (1H, ddd, J=7.8, 7.5, 1.8 Hz), 7.17 (1H, br d, J=7.8 Hz), 7.04
(1H, td, J=7.5, 0.8 Hz), 6.89 (1H, d, J=8.1 Hz), 5.64 (1H, s), 5.26
(2H, s), 3.94 (3H, s), 3.49 (3H, s), 3.40 (2H, t, J=7.2 Hz), 2.99
(2H, t, J=7.2 Hz)
Example 233
Using
3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-methoxymethoxyphe-
nyl)propan-1-one obtained in Example 232, colorless oily
3-[2-(3-isopropoxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-methoxymethoxyphenyl-
)propan-1-one was obtained in the same manner as in Example
102.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.66 (1H, dd, J=7.5, 1.8 Hz),
7.57 (1H, dd, J=8.4, 1.8 Hz), 7.53 (1H, d, J=1.8 Hz), 7.42 (1H,
ddd, J=8.4, 7.5, 1.8 Hz), 7.41 (1H, s), 7.17 (1H, dd, J=8.4, 1.2
Hz), 7.04 (1H, td, J=7.5, 1.2 Hz), 6.91 (1H, d, J=8.4 Hz), 5.26
(2H, s), 4.64 (1H, sept, J=6.0 Hz), 3.90 (3H, s), 3.49 (3H, s),
3.40 (2H, t, J=7.2 Hz), 3.00 (2H, t, J=7.2 Hz), 1.39 (6H, d, J=6.0
Hz)
Example 234
Using 0.76 g of 4-chloromethyl-2-(3-ethoxy-4-methoxyphenyl)oxazole
obtained in Reference Example 58, 60 mg of white powdery
3-[2-(3-ethoxy-4-methoxyphenyl)oxazol-4-yl]-1-[2-(2,2,2-trifluoroethoxy)p-
henyl]propan-1-one was obtained in the same manner as in Example
228.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.76 (1H, dd, J=7.8, 2.1 Hz),
7.58-7.48 (3H, m), 7.39 (1H, s), 7.12 (1H, t, J=7.5 Hz), 6.92-6.88
(2H, m), 4.46 (2H, q, J=7.8 Hz), 4.18 (2H, q, J=7.2 Hz), 3.92 (3H,
s), 3.40 (2H, t, J=7.5 Hz), 3.00 (2H, t, J=7.5 Hz), 1.49 (3H, t,
J=7.2 Hz)
Example 235
Using 0.76 g of 4-chloromethyl-2-(3-ethoxy-4-methoxyphenyl)oxazole
obtained in Reference Example 58 and 0.58 g of
1-(2-trifluoromethoxyphenyl)ethanone, 0.18 g of pale yellow oily
3-[2-(3-ethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-trifluoro
methoxyphenyl)propan-1-one was obtained in the same manner as in
Example 228.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.71 (1H, dd, J=7.5, 1.8 Hz),
7.58-7.50 (3H, m), 7.42 (1H, s), 7.38-7.30 (2H, m), 6.91 (1H, d,
J=8.4 Hz), 4.17 (2H, q, J=6.6 Hz), 3.91 (3H, s), 3.45 (2H, t, J=7.2
Hz), 3.01 (2H, t, J=7.2 Hz), 1.49 (3H, t, J=6.6 Hz)
Example 236
Using 0.5 g of 3-[2-(3,4-dimethoxyphenyl)oxazol-4-yl]propionic acid
obtained in Reference Example 71, 0.32 g of white powdery
3-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-1-pyrrolidin-1-yl-propan-1-one
was obtained in the same manner as in Example 1.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.55 (1H, dd, J=6.75, 1.8 Hz),
7.52 (1H, d, J=1.8 Hz), 7.44 (1H, s), 6.91 (1H, d, J=8.1 Hz),
4.20-4.10 (4H, m), 3.50-3.40 (4H, m), 3.00-2.90 (2H, m), 2.70-2.60
(2H, m), 1.95-1.75 (4H, m), 1.48 (3H, t, J=7.2 Hz), 1.48 (3H, t,
J=7.2 Hz)
Example 237
Using 0.3 g of 3-[2-(3,4-dimethoxyphenyl)oxazol-4-yl]propionic acid
obtained in Reference Example 71, 0.28 g of white powdery
3-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-1-(3-hydroxy
pyrrolidin-1-yl)propan-1-one was obtained in the same manner as in
Example 1.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.55 (1H, dd, J=6.75, 1.8 Hz),
7.52 (1H, d, J=1.8 Hz), 7.44 (1H, s), 6.91 (1H, d, J=8.1 Hz),
4.20-4.10 (4H, m), 3.50-3.40 (4H, m), 3.00-2.90 (2H, m), 2.70-2.60
(2H, m), 2.10-1.90 (3H, m), 1.48 (3H, t, J=6.9 Hz), 1.48 (3H, t,
J=6.9 Hz)
Example 238
Using 1 g of
3-[2-(4-benzyloxy-3-methoxyphenyl)oxazol-4-yl]propionic acid
obtained in Reference Example 73, 1.03 g of pale yellow powdery
3-[2-(4-benzyloxy-3-methoxyphenyl)oxazol-4-yl]-1-pyrrolidin-1-ylpropan-1--
one was obtained in the same manner as in Example 1.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.61-7.27 (8H, m), 6.93 (1H, d,
J=8.4 Hz), 5.20 (2H, s), 3.97 (3H, s), 3.49-3.39 (4H, m), 2.94 (2H,
t, J=7.5 Hz), 2.65 (2H, t, J=7.5 Hz), 1.95-1.78 (4H, m)
Example 239
Using 1 g of
3-[2-(4-benzyloxy-3-methoxyphenyl)oxazol-4-yl]-1-pyrrolidin-1-yl-propan-1-
-one obtained in Example 238, 0.59 g of white powdery
3-[2-(4-hydroxy-3-methoxyphenyl)oxazol-4-yl]-1-pyrrolidin-1-ylpropan-1-on-
e was obtained in the same manner as in Example 2.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.56-7.51 (2H, m), 7.44 (1H, s),
6.90 (1H, d, J=8.4 Hz), 5.97 (1H, s), 3.97 (3H, s), 3.49-3.39 (4H,
m), 2.94 (2H, t, J=7.5 Hz), 2.66 (2H, t, J=7.5 Hz), 1.97-1.79 (4H,
m)
Example 240
Using 0.15 g of
3-[2-(4-hydroxy-3-methoxyphenyl)oxazol-4-yl]-1-pyrrolidin-1-yl-propan-1-o-
ne obtained in Example 239, 0.13 g of white powdery
3-[2-(4-ethoxy-3-methoxyphenyl)oxazol-4-yl]-1-pyrrolidin-1-ylpropan-1-one
was obtained in the same manner as in Example 3.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.57 (1H, dd, J=8.1, 2.1 Hz),
7.52 (1H, d, J=1.8 Hz), 7.45 (1H, s), 6.91 (1H, d, J=8.1 Hz), 4.15
(2H, q, J=6.9 Hz), 3.96 (3H, s), 3.49-3.40 (4H, m), 2.94 (2H, t,
J=7.2 Hz), 2.66 (2H, t, J=7.2 Hz), 1.97-1.79 (4H, m), 1.49 (3H, t,
J=6.9 Hz)
Example 241
N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-trifluoro-
methylbenzamide obtained in Example 25 was dissolved in 1 ml of
dimethylformamide. A 30 mg quantity of sodium hydride was added
thereto with ice-cooling and stirring, and the mixture was stirred
for 30 minutes. A 30 mg quantity of methyl iodide was added
thereto, and the reaction mixture was stirred at room temperature
for 2 hours. Water and ethyl acetate were then added thereto, and
extraction was performed. The organic layer was washed with water
twice and concentrated by removing the solvent under reduced
pressure. The residue was purified by silica gel chromatography
(n-hexane:ethyl acetate=3:1) to give 35 mg of colorless oily
N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-N-methyl-2--
trifluoromethylbenzamide.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.72-7.34 (7H, m), 6.94 (1H, dd,
J=8.4, 1.8 Hz), 4.88-4.11 (1H, m), 3.98-3.89 (5H, m), 3.17-2.88
(3H, m), 1.43-1.34 (1H, m), 0.71-0.64 (2H, m), 0.42-0.36 (2H,
m)
Example 242
Using 0.14 g of
[2-(3,4-diethoxyphenyl)oxazol-4-ylmethyl]methylamine obtained in
Reference Example 74, 70 mg of colorless oily
N-[2-(3,4-dimethoxyphenyl)oxazol-4-ylmethyl]-2-ethoxy-N-methylbenzamide
was obtained in the same manner as in Example 1.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.60-7.26 (5H, m), 7.00-6.87 (3H,
m), 4.23-4.02 (8H, m), 3.19-2.96 (3H, m), 1.52-1.40 (6H, m), 1.36
(3H, t, J=6.9 Hz)
Example 243
Using 0.2 g of 2-[2-(3,4-diethoxyphenyl)oxazol-4-yl]ethylamine
obtained in Reference Example 78 and 0.18 g of 2-ethoxy benzoic
acid, 0.14 g of white powdery
N-{2-[2-(3,4-dimethoxyphenyl)oxazol-4-yl]ethyl}-2-ethoxybenzamide
was obtained in the same manner as in Example 1.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.22 (1H, dd, J=7.5, 4.8 Hz),
7.60-7.50 (2H, m), 7.47 (1H, s), 7.39 (1H, m), 7.06 (1H, m),
6.95-6.85 (2H, m), 4.30-4.05 (6H, m), 4.09 (2H, q, J=6.9 Hz), 3.85
(2H, q, J=6.6 Hz), 2.91 (2H, t, J=6.6 Hz), 1.48 (6H, t, J=6.9 Hz),
1.28 (6H, t, J=6.9 Hz)
Example 244
Using 0.3 g of 2-(3,4-diethoxyphenyl)oxazole-4-carboxylic acid
obtained in Reference Example 80 and 0.28 g of 1-(2-amino)ethanone,
0.32 g of white powdery
N-(2-oxo-2-phenylethyl)-2-(3,4-diethoxyphenyl)oxazole-4-carboxamide
was obtained in the same manner as in Example 1.
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 8.67 (1H, d, J=0.9 Hz), 8.49
(1H, t, J=5.7 Hz), 8.10-8.00 (2H, m), 7.70-7.50 (5H, m), 7.16 (1H,
m), 4.81 (2H, d, J=5.7 Hz), 4.13 (4H, q, J=6.9 Hz), 1.38 (6H, t,
J=6.9 Hz), 1.37 (3H, t, J=6.9 Hz)
Example 245
Using 2-(3,4-diethoxyphenyl)oxazole-4-carboxylic acid obtained in
Reference Example 80, 0.32 g of white powdery
1-(4-{4-[2-(3,4-diethoxyphenyl)oxazole-4-carbonyl]piperazin-1-yl}phenyl)e-
thanone was obtained in the same manner as in Example 1.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.20 (1H, s), 7.95-7.85 (2H, m),
7.62 (1H, dd, J=8.4, 2.1 Hz), 7.54 (1H, d, J=2.1 Hz), 7.00-6.85
(3H, m), 4.40-4.20 (2H, m), 4.19 (2H, q, J=6.9 Hz), 4.16 (2H, q,
J=6.9 Hz), 4.00-3.80 (2H, m), 3.50-3.45 (4H, m), 2.53 (3H, s), 1.50
(3H, t, J=6.9 Hz), 1.50 (3H, t, J=6.9 Hz)
Example 246
Using 0.28 g of 2-(3,4-diethoxyphenyl)oxazole-4-carboxylic acid
obtained in Reference Example 80 and 0.2 g of
1-(4-methoxyphenyl)piperazine, 0.36 g of white powdery
4-(2-(3,4-diethoxyphenyl)oxazol-4-yl)-1-(4-methoxyphenyl)piperazine
was obtained in the same manner as in Example 1.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.16 (1H, s), 7.61 (1H, dd,
J=8.7, 2.1 Hz), 7.54 (1H, s), 6.95-6.84 (5H, m), 4.40-4.30 (2H, m),
4.21-4.12 (4H, m), 4.00-3.93 (2H, m), 3.78 (3H, s), 3.14 (4H, t,
J=4.8 Hz), 1.47 (6H, t, J=7.2 Hz)
Example 247
Using 0.28 g of 2-(3,4-diethoxyphenyl)oxazole-4-carboxylic acid
obtained in Reference Example 80 and 1-(4-hydroxyphenyl)piperazine,
white powdery
4-(2-(3,4-diethoxyphenyl)oxazol-4-yl)-1-(4-hydroxyphenyl)piperazine
was obtained in the same manner as in Example 1.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.16 (1H, s), 7.61 (1H, dd,
J=8.7, 2.1 Hz), 7.54 (1H, s), 6.95-6.78 (5H, m), 4.40-4.30 (2H, m),
4.21-4.12 (4H, m), 4.00-3.93 (2H, m), 3.14 (4H, t, J=4.8 Hz), 1.49
(6H, t, J=7.2 Hz)
Example 248
Using 0.28 g of 2-(3,4-diethoxyphenyl)oxazole-4-carboxylic acid
obtained in Reference Example 80 and 0.14 g of 2-phenylethylamine,
0.21 g of white powdery
N-phenethyl-2-(3,4-dimethoxyphenyl)oxazole-4-carboxamide was
obtained in the same manner as in Example 1.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.17 (1H, s), 7.56 (1H, dd,
J=8.4, 2.1 Hz), 7.50 (1H, d, J=2.1 Hz), 7.36-7.21 (5H, m), 7.12
(1H, br s), 6.93 (1H, d, J=8.4 Hz), 4.22-4.12 (4H, m), 3.74-3.66
(2H, m), 2.95 (2H, t, J=7.2 Hz), 1.57-1.46 (6H, m)
Example 249
Using 0.28 g of 2-(3,4-diethoxyphenyl)oxazole-4-carboxylic acid
obtained in Reference Example 80 and 0.13 g of
1-(2-aminoethyl)pyrrolidine, 0.15 g of pale yellow powdery
N-(2-(pyrrolidin-1-yl)ethyl)-2-(3,4-dimethoxyphenyl)oxazole-4-carboxamide
was obtained in the same manner as in Example 1.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.17 (1H, s), 7.60 (1H, dd,
J=8.4, 1.8 Hz), 7.55 (1H, d, J=1.8 Hz), 7.44 (1H, br s), 6.92 (1H,
d, J=8.4 Hz), 4.23-4.12 (4H, m), 3.65-3.58 (2H, m), 2.79 (2H, t,
J=6.6 Hz), 2.70-2.58 (4H, m), 1.87-1.75 (4H, m), 1.53-1.46 (6H,
m)
Example 250
Using 0.15 g of [2-(3,4-diethoxyphenyl)oxazol-4-yl]acetic acid
obtained in Reference Example 81 and 0.11 g of o-phenetidine, 0.12
g of white powdery
2-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-N-(2-ethoxyphenyl)acetamide
was obtained in the same manner as in Example 1.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.74 (1H, br s), 8.37 (1H, dd,
J=7.2, 1.8 Hz), 7.70-7.65 (2H, m), 7.61 (1H, d, J=1.8 Hz),
7.00-6.90 (3H, m), 6.80 (1H, dd, J=7.8, 1.2 Hz), 4.18 (2H, q, J=6.9
Hz), 4.16 (2H, q, J=6.9 Hz), 3.97 (2H, q, J=7.2 Hz), 3.74 (2H, s),
1.49 (3H, t, J=6.9 Hz), 1.49 (3H, t, J=6.9 Hz), 1.18 (3H, t, J=7.2
Hz)
Example 251
Using 0.15 g of [2-(3,4-diethoxyphenyl)oxazol-4-yl]acetic acid
obtained in Reference Example 81 and 85 mg of
2-amino-3-hydroxypyridine, 0.11 g of white powdery
2-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-N-(3-hydroxypyridin-2-yl)acetamide
was obtained in the same manner as in Example 1.
.sup.1H-NMR (CDCl.sub.3) .delta.: 10.37 (1H, brs), 9.88 (1H, brs),
7.84 (1H, dd, J=4.8, 1.2 Hz), 7.65-7.60 (3H, m), 7.31 (1H, dd,
J=4.2, 1.2 Hz), 6.94 (1H, d, J=9.0 Hz), 4.22 (2H, q, J=6.9 Hz),
4.16 (2H, q, J=6.9 Hz), 1.51 (3H, t, J=6.9 Hz), 1.49 (3H, t, J=6.9
Hz)
Example 252
A 0.5 g quantity of 4-chloromethyl-2-(3,4-diethoxyphenyl)oxazole
obtained in Reference Example 35, 0.36 g of piperazin-2-one and
0.28 g of potassium carbonate were added to 10 ml of acetonitrile,
and the mixture was heated and refluxed for 7 hours. The residue
was diluted with ethyl acetate, and washed with water and then with
saturated brine. The organic layer was dried over anhydrous
magnesium sulfate and concentrated by removing the solvent under
reduced pressure. The residue was purified by silica gel column
chromatography (dichloromethane:methanol=1:0 to 50:1), and the
obtained crude crystals were recrystallized from ethyl acetate to
give 0.25 g of colorless crystalline
4-[2-(3,4-diethoxyphenyl)oxazol-4-ylmethyl]piperazin-2-one.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.59 (1H, d, J=8.1, 2.1 Hz), 7.56
(1H, d, J=2.1 Hz), 6.91 (1H, d, J=8.1 Hz), 6.03 (1H, brs), 4.17
(2H, q, J=6.9 Hz), 4.15 (2H, q, J=6.9 Hz), 3.61 (2H, s), 3.45-3.35
(2H, m), 3.27 (2H, s), 2.80-2.75 (2H, m), 1.48 (6H, t, J=6.9
Hz)
Example 253
Using 0.5 g of 4-chloromethyl-2-(3,4-diethoxyphenyl)oxazole
obtained in Reference Example 35 and 0.5 g of morpholine, 0.31 g of
white powdery 4-[2-(3,4-diethoxyphenyl)oxazol-4-ylmethyl]morpholine
was obtained in the same manner as in Example 252.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.70-7.50 (2H, m), 7.54 (1H, s),
6.91 (1H, d, J=8.4 Hz), 4.25-4.10 (4H, m), 3.80-3.70 (4H, m), 3.51
(2H, s), 2.60-2.50 (4H, m), 1.48 (6H, t, J=6.9 Hz)
Example 254
A 0.5 g quantity of 4-chloromethyl-2-(3,4-diethoxy phenyl)oxazole
obtained in Reference Example 35, 0.28 g of 2-mercaptopyridine and
0.28 g of potassium carbonate were added to 10 ml of
dimethylformamide, and the mixture was stirred at room temperature
for 24 hours. The reaction mixture was diluted with ethyl acetate,
and washed with water and then with saturated brine. The organic
layer was dried over anhydrous magnesium sulfate and concentrated
by removing the solvent under reduced pressure. The residue was
purified by silica gel column chromatography (ethyl
acetate:n-hexane=1:4 to 1:2), and the obtained crude crystals were
recrystallized from a mixture of ethyl acetate and n-hexane to give
0.63 g of colorless crystalline
2-[2-(3,4-diethoxyphenyl)oxazol-4-ylmethylsulfanyl]pyridine.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.45 (3H, m), 7.60-7.50 (3H, m),
7.47 (1H, m), 7.18 (1H, d, J=8.1 Hz), 6.99 (1H, m), 6.89 (1H, d,
J=8.1 Hz), 4.38 (2H, s), 4.17 (2H, q, J=6.9 Hz), 4.14 (2H, q, J=6.9
Hz), 1.47 (6H, t, J=6.9 Hz)
Example 255
A 0.58 g quantity of
2-[2-(3,4-diethoxyphenyl)oxazol-4-ylmethylsulfanyl]pyridine
obtained in Example 254 was added to 20 ml of dichloromethane. A
0.55 g quantity of m-chloroperbenzoic acid was gradually added
thereto with ice-cooling, and the mixture was then stirred. The
reaction mixture was diluted with 30 ml of dichloromethane, and
washed with an aqueous 10% sodium hydroxide solution and then with
saturated brine. The organic layer was dried over anhydrous
magnesium sulfate and concentrated by removing the solvent under
reduced pressure. The residue was purified by silica gel column
chromatography (ethyl acetate:n-hexane=2:1 to 3:1), and the
obtained crude crystals was recrystallized from a mixture of ethyl
acetate and n-hexane to give 0.49 g of colorless crystalline
2-[2-(3,4-diethoxyphenyl)oxazol-4-ylmethanesulfonyl]pyridine.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.81 (1H, m), 8.00 (1H, m), 7.91
(1H, m), 7.61 (1H, s), 7.55 (1H, m), 7.50-7.40 (2H, m), 6.87 (1H,
d, J=8.4 Hz), 4.71 (2H, s), 4.13 (4H, q, J=6.9 Hz), 1.47 (6H, t,
J=6.9 Hz)
Example 256
A 0.27 g quantity of [2-(3,4-diethoxyphenyl)oxazol-4-yl]methylamine
obtained in Reference Example 37 and 0.3 ml of triethylamine were
dissolved in 10 ml of acetonitrile. A 0.19 g quantity of
o-toluenesulfonylchloride was added thereto, and the mixture was
stirred at room temperature for 1 hour. Water was added to the
reaction mixture, and extraction was performed with ethyl acetate.
The organic layer was washed with water twice, and the solvent was
removed. The obtained residue was purified using a silica gel
column (n-hexane:ethyl acetate=1:1). The obtained crude crystals
were recrystallized from a mixture of n-hexane and ethyl acetate to
give 0.3 g of white powdery
N-[2-(3,4-diethoxyphenyl)oxazol-4-ylmethyl]-2-methylbenzenesulfonamide.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.96 (1H, dd, J=7.5, 1.5 Hz),
7.48-7.16 (6H, m), 6.90 (1H, d, J=8.4 Hz), 5.11 (1H, br s),
4.21-4.11 (6H, m), 2.64 (3H, s), 1.52-1.46 (6H, m)
Example 257
A 0.5 g quantity of
3-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl-
)propan-1-one obtained in Example 102 and 0.18 ml of hydrazine
monohydrate were added to diethylene glycol. A 0.14 g quantity of
potassium hydroxide was added thereto, and the mixture was stirred
at 150.degree. C. for 1 hour. The reaction mixture was allowed to
cool, water was then added thereto, and extraction was performed
with ethyl acetate. Drying was performed with anhydrous magnesium
sulfate, and the solvent was removed. The residue was purified by
silica gel column chromatography (n-hexane:ethyl acetate=4:1) to
give 0.1 g of colorless oily
2-(3-cyclopropylmethoxy-4-methoxyphenyl)-4-[3-(2-ethoxyphenyl)propyl]oxaz-
ole.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.58 (1H, dd, J=8.4, 1.8 Hz),
7.51 (1H, d, J=1.8 Hz), 7.39 (1H, s), 7.17-7.12 (2H, m), 6.93-6.81
(3H, m), 4.03 (2H, q, J=6.9 Hz), 3.94-3.92 (5H, m), 2.72 (2H, t,
J=7.5 Hz), 2.62 (2H, t, J=7.5 Hz), 2.03-1.96 (2H, m), 1.43-1.25
(4H, m), 0.69-0.63 (2H, m), 0.40-0.35 (2H, m)
Example 258
A 1.6 g quantity of sodium hydride was suspended in 100 ml of
tetrahydrofuran. A 2.68 g quantity of 1-(2-methylphenyl)ethanone
and 6.58 g of 2-(3-benzyloxy-4-methoxyphenyl)-4-chloro
methyloxazole obtained in Reference Example 5 were successively
added thereto with ice-cooling and stirring, and the mixture was
heated and refluxed for 4 hours. An aqueous saturated ammonium
chloride solution was added thereto with ice-cooling. After
stirring for 15 minutes, water was added thereto, and extraction
was performed with ethyl acetate. Drying was then performed with
anhydrous magnesium sulfate, and the solvent was removed. The
residue was purified by silica gel column chromatography
(n-hexane:ethyl acetate=4:1), and 1.6 g of the obtained crude
product was dissolved in 20 ml of ethanol. A 0.16 g quantity of 10%
palladium-carbon powder was added thereto, and the mixture was
stirred under a hydrogen atmosphere for 18 hours. The reaction
mixture was filtered, and the obtained filtrate was concentrated.
The residue was purified by silica gel column chromatography
(dichloromethane:ethanol=100:1) to give 0.47 g of yellow oily
2-(3-hydroxy-4-methoxyphenyl)-4-(3-o-tolyl propyl)oxazole.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.60-7.54 (2H, m), 7.38 (1H, s),
7.15-7.08 (4H, m), 6.90 (1H, d, J=8.4 Hz), 5.65 (1H, s), 3.94 (3H,
s), 2.72-2.62 (4H, m), 2.37 (3H, s)
Example 259
Using 0.47 g of
2-(3-hydroxy-4-methoxyphenyl)-4-(3-o-tolylpropyl)oxazole obtained
in Example 258, 0.37 g of colorless oily
2-(3-cyclopropylmethoxy-4-methoxyphenyl)-4-(3-o-tolylpropyl)oxazole
was obtained in the same manner as in Example 111.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.58 (1H, dd, J=8.1, 2.1 Hz),
7.51 (1H, d, J=2.1 Hz), 7.38 (1H, s), 7.15-7.08 (4H, m), 6.92 (1H,
d, J=8.1 Hz), 3.94-3.92 (5H, m), 2.72-2.62 (4H, m), 2.31 (3H, s),
2.04-1.92 (2H, m), 1.40-1.35 (1H, m), 0.69-0.63 (2H, m), 0.40-0.35
(2H, m)
Example 260
A 0.21 g quantity of
3-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl-
)propan-1-one obtained in Example 102 was added to 5 ml of ethanol,
and the mixture was stirred with ice-cooling. A 37 mg quantity of
sodium borohydride was gradually added thereto. After the
temperature of the reaction mixture had reached room temperature,
stirring was performed for 2 hours. An aqueous 5N hydrochloric acid
solution was added to the reaction mixture, and solvent was then
removed. Extraction was performed with dichloromethane, and the
extract was washed with saturate brine. The extract was then dried
over anhydrous magnesium sulfate, the solvent was removed, and the
residue was purified by silica gel column chromatography
(n-hexane:ethyl acetate=3:1) to give 0.18 g of colorless oily
3-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl-
)propan-1-ol.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.58 (1H, dd, J=8.4, 2.1 Hz),
7.50 (1H, d, J=1.8 Hz), 7.39-7.35 (2H, m), 7.23-7.18 (1H, m),
6.97-6.84 (3H, m), 5.00 (1H, br s), 4.07 (2H, q, J=6.6 Hz),
3.94-3.92 (5H, m), 3.44 (1H, br s), 2.80-2.60 (2H, m), 2.20-2.15
(2H, m), 1.43-1.37 (4H, m), 0.69-0.63 (2H, m), 0.40-0.37 (2H,
m)
Example 261
An 80 mg quantity of 3-[2-(3-isopropoxy-4-methoxy
phenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one obtained
in Example 139 was dissolved in 3 ml of dimethylformamide. A 0.2 g
quantity of sodium hydride was added thereto with ice-cooling and
stirring, and the mixture was stirred for 30 minutes. A 75 mg
quantity of methyl iodide was added thereto, and the reaction
mixture was stirred at room temperature for 8 hours. Water was
added to the reaction mixture, and extraction was performed with
ethyl acetate. The organic layer was washed with water twice, and
the solvent was removed. The obtained residue was purified using a
silica gel column (n-hexane:ethyl acetate=3:1) to give 35 mg of
colorless oily
3-[2-(3-isopropoxy-4-methoxyphenyl)oxazol-4-yl]-2,2-dimethyl-1-(3-methylp-
yridin-2-yl)propan-1-one.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.41 (1H, dd, J=4.5, 1.2 Hz),
7.38-7.60 (3H, m), 7.34 (1H, s), 7.21-7.24 (1H, m), 6.90 (1H, d,
J=8.7 Hz), 4.63 (1H, sept., J=6.0 Hz), 3.94 (3H, s), 3.15 (2H, s),
2.28 (3H, s), 1.38-1.49 (12H, m)
Example 262
Using 0.9 g of methyl
3-{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-yl}propionate
obtained in Reference Example 83, 1.05 g of yellow oily methyl
3-(3-methoxypyridin-2-yl)-2-{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl-
]oxazol-4-ylmethyl}-3-oxopropinate was obtained in the same manner
as in Example 100.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.25 (1H, dd, J=4.5, 1.5 Hz),
7.65 (1H, dd, J=8.4, 2.1 Hz), 7.55 (1H, d, J=2.1 Hz), 7.47-7.33
(3H, m), 6.94 (1H, d, J=8.4 Hz), 5.17 (1H, t, J=6.9 Hz), 4.43 (2H,
q, J=8.4 Hz), 3.93 (3H, s), 3.92 (3H, s), 3.65 (3H, s), 3.32-3.23
(2H, m)
Example 263
Using 0.7 g of methyl
3-(3-methoxypyridin-2-yl)-2-{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl-
]oxazol-4-ylmethyl}-3-oxopropionate obtained in Example 262, 0.42 g
of colorless oily methyl
2-{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-ylmethyl}-2-meth-
yl-3-(3-methylpyridin-2-yl)-3-oxopropinate was obtained in the same
manner as in Example 261.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.18 (1H, dd, J=6.9, 1.8 Hz),
7.64 (1H, dd, J=8.4, 2.1 Hz), 7.54 (1H, d, J=2.1 Hz), 7.42-7.34
(3H, m), 6.93 (1H, d, J=8.7 Hz), 4.43 (2H, q, J=8.4 Hz), 3.93 (3H,
s), 3.91 (3H, s), 3.64 (3H, s), 3.40 (1H, d, J=15 Hz), 3.26 (1H, d,
J=15 Hz)
Example 264
Using 0.42 g of methyl
2-{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-ylmethyl}-2-meth-
yl-3-(3-methyl pyridin-2-yl)-3-oxopropinate obtained in Example
263, 0.25 g of colorless oily
1-(3-methoxypyridin-2-yl)-3-{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl-
]oxazol-4-yl}-2-methylpropan-1-one was obtained in the same manner
as in Example 136.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.24 (1H, dd, J=4.5, 1.5 Hz),
7.67 (1H, dd, J=8.4, 2.1 Hz), 7.57 (1H, d, J=2.1 Hz), 7.43-7.28
(3H, m), 6.94 (1H, d, J=8.7 Hz), 4.45 (1H, q, J=8.4 Hz), 4.21 (1H,
q, J=6.9 Hz), 3.91 (3H, s), 3.88 (3H, s), 3.15-3.06 (1H, m),
2.73-2.64 (1H, m), 1.23 (3H, d, J=7.2 Hz)
Example 265
Using 0.2 g of
1-(3-methoxypyridin-2-yl)-3-{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl-
]oxazol-4-y}-2-methyl propan-1-one obtained in Example 264, 80 mg
of colorless oily
1-(3-methoxypyridin-2-yl)-3-{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl-
]oxazol-4-yl}-2,2-dimethylpropan-1-one was obtained in the same
manner as in Example 261.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.17 (1H, dd, J=4.5, 1.5 Hz),
7.70 (1H, dd, J=8.4, 1.8 Hz), 7.60 (1H, d, J=1.8 Hz), 7.31-7.21
(2H, m), 6.96 (1H, d, J=8.4 Hz), 4.45 (2H, q, J=8.4 Hz), 3.92 (3H,
s), 3.78 (3H, s), 3.05 (2H, s), 1.34 (6H, s)
Example 266
A 60 ml quantity of trifluoroacetic acid was stirred with ice
cooling, 12.3 g of the compound obtained in Example 231 was added
thereto, and stirring was conducted for one hour. At the completion
of the reaction, the reaction mixture was neutralized by addition
of an aqueous saturated sodium bicarbonate solution, and ethyl
acetate was added to the obtained mixture. The organic layer was
washed twice with water, separated, concentrated under reduced
pressure, and the obtained crude crystals were recrystallized from
ethanol, thereby yielding 5.9 g of white powdery
3-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-hydroxyphenyl)propan--
1-one.
.sup.1H-NMR (CDCl.sub.3) .delta.: 12.2 (1H, s), 7.81 (1H, d, J=8.1
Hz), 7.62-7.26 (9H, m), 6.99-6.85 (3H, m), 5.19 (2H, s), 3.92 (3H,
s), 3.43 (2H, t, J=7.5 Hz), 3.02 (2H, t, J=7.5 Hz)
Example 267
Using the compound obtained in Example 266 and
chlorodifluoromethane, white powdery 3-[2-(3-benzyloxy-4-methoxy
phenyl)oxazol-4-yl]-1-(2-difluoromethoxyphenyl)propan-1-one was
obtained following the procedure of Example 19.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.71 (1H, dd, J=7.8, 1.8 Hz),
7.90-6.60 (7H, m), 6.34 (1H, t, J=73.8 Hz), 5.20 (2H, s), 3.92 (3H,
s), 3.36 (2H, t, J=7.2 Hz), 2.29 (2H, t, J=7.2 Hz)
Reference Example 84
Using 2-fluoroethanol, a colorless oily 2-fluoroethyl
methanesulfonate was obtained following the procedure of Reference
Example 50.
.sup.1H-NMR (CDCl.sub.3) .delta.: 4.76-4.73 (1H, m), 4.60-4.58 (1H,
m), 4.53-4.50 (1H, m), 4.43-4.41 (1H, m), 3.08 (3H, s)
Reference Example 85
Using 2,2-difluoroethanol, colorless oily 2,2-difluoro
ethylmethanesulfonate was obtained following the procedure of
Reference Example 50.
.sup.1H-NMR (CDCl.sub.3) .delta.: 6.01 (1H, tt, J=54.3, 3.9 Hz),
4.38 (2H, td, J=12.9, 3.9 Hz), 3.12 (3H, s)
Example 268
Using the compound obtained in Example 266 and the compound
obtained in Reference Example 84, white powdery
3-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-yl]-1-[2-(2-fluoroethoxy)pheny-
l]propan-1-one was obtained following the procedure of Example
3.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.74 (1H, dd, J=7.8, 1.8 Hz),
7.61-7.59 (2H, m), 7.49-7.31 (7H, m), 7.07 (1H, t, J=7.8 Hz), 6.92
(2H, d, J=8.7 Hz), 5.20 (2H, s), 4.90-4.87 (1H, m), 4.74-4.71 (1H,
m), 4.37-4.35 (1H, m), 4.28-4.26 (1H, m), 3.92 (3H, s), 3.44 (2H,
t, J=7.5 Hz), 2.99 (2H, t, J=7.5 Hz)
Example 269
Using the compound obtained in Example 266 and the compound
obtained in Reference Example 85, white powdery
3-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-yl]-1-[2-(2,2-difluoroethoxy)p-
henyl]propan-1-one was obtained following the procedure of Example
3.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.74 (1H, dd, J=7.8, 1.8 Hz),
7.61-7.28 (9H, m), 7.08 (1H, t, J=7.8 Hz), 6.95-6.89 (2H, m), 6.22
(1H, tt, J=54.9, 3.9 Hz), 5.19 (2H, s), 4.29 (1H, td, J=12.9, 3.9
Hz), 3.92 (3H, s), 3.38 (2H, t, J=7.5 Hz), 2.98 (2H, t, J=7.5
Hz)
Example 270
Using the compound obtained in Example 267, white powdery
1-(2-difluoromethoxyphenyl)-3-[2-(3-hydroxy-4-methoxy
phenyl)oxazol-4-yl]propan-1-one was obtained following the
procedure of Example 2.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.71 (1H, t, J=7.5 Hz), 7.54-7.41
(4H, m), 7.38-7.16 (2H, m), 6.89 (1H, d, J=8.1 Hz), 6.59 (1H, t,
J=74.7 Hz), 5.69 (1H, s), 3.93 (3H, s), 3.36 (2H, t, J=7.2 Hz),
2.99 (2H, t, J=7.2 Hz)
Example 271
Using the compound obtained in Example 268, white powdery
1-[2-(2-fluoroethoxy)phenyl]-3-[2-(3-hydroxy-4-methoxy
phenyl)oxazol-4-yl]propan-1-one was obtained following the
procedure of Example 2.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.73 (1H, dd, J=7.8, 1.8 Hz),
7.55-7.42 (4H, m), 7.05 (1H, t, J=7.8 Hz), 6.91 (2H, d, J=8.7 Hz),
4.91-4.88 (1H, m), 4.75-4.72 (1H, m), 4.38-4.35 (1H, m), 4.29-4.26
(1H, m), 3.94 (3H, s), 3.43 (2H, t, J=7.5 Hz), 2.99 (2H, t, J=7.5
Hz)
Example 272
Using the compound obtained in Example 269, white powdery
1-[2-(2,2-difluoroethoxy)phenyl]-3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-
-yl]propan-1-one was obtained following the procedure of Example
2.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.73 (1H, dd, J=7.8, 1.8 Hz),
7.56-7.41 (4H, m), 7.08 (1H, t, J=7.8 Hz), 6.92-6.87 (2H, m), 6.21
(1H, tt, J=54.9, 3.9 Hz), 5.67 (1H, s), 4.29 (1H, td, J=12.9, 3.9
Hz), 3.94 (3H, s), 3.38 (2H, t, J=7.2 Hz), 2.98 (2H, t, J=7.2
Hz)
Example 273
Using the compound obtained in Example 270 and 2-bromopropane,
white powdery
1-(2-difluoromethoxyphenyl)-3-[2-(3-isopropoxy-4-methoxyphenyl)ox-
azol-4-yl]propan-1-one was obtained following the procedure of
Example 3.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.70-7.25 (5H, m), 7.20-6.80 (2H,
m), 6.59 (1H, t., J=73.5 Hz), 4.64 (1H, m), 3.93 (3H, s), 1.39 (3H,
d, J=6.0 Hz)
Example 274
Using the compound obtained in Example 270 and ethyl iodide, white
powdery
1-(2-difluoromethoxyphenyl)-3-[2-(3-ethoxy-4-methoxyphenyl)oxazol-
-4-yl]propan-1-one was obtained following the procedure of Example
3.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.71 (1H, dd, J=7.8, 1.8 Hz),
7.60-7.46 (3H, m), 7.42 (1H, s), 7.31-7.16 (2H, m), 6.91 (1H, d,
J=8.1 Hz), 6.59 (1H, t, J=73.5 Hz), 4.18 (2H, q, J=7.2 Hz), 3.92
(3H, s), 3.37 (2H, t, J=7.2 Hz), 3.00 (2H, t, J=7.2 Hz), 1.49 (3H,
t, J=7.2 Hz)
Example 275
Using the compound obtained in Example 271 and 2-bromopropane,
white powdery
1-(2-fluoroethoxyphenyl)-3-[2-(3-isopropoxy-4-methoxyphenyl)oxazo-
l-4-yl]propan-1-one was obtained following the procedure of Example
3.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.73 (1H, d, J=7.2 Hz), 7.58-7.54
(2H, m), 7.45-7.41 (2H, m), 7.04 (1H, t, J=7.2 Hz), 6.92 (2H, t,
J=8.1 Hz), 4.81 (2H, dt, J=47.4, 4.2 Hz), 4.64-4.60 (1H, m), 4.32
(2H, dt, J=23.1, 4.2 Hz), 3.89 (3H, s), 3.43 (2H, t, J=7.2 Hz),
3.00 (2H, t, J=7.2 Hz), 1.39 (6H, d, J=5.7 Hz)
Example 276
Using the compound obtained in Example 271 and 4-bromo-1-butene,
white powdery
3-[2-(3-but-3-enyloxy-4-methoxyphenyl)oxazol-4-yl]-1-[2-(2-fluoro-
ethoxy)phenyl]propan-1-one was obtained following the procedure of
Example 3.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.73 (1H, d, J=7.5 Hz), 7.58-7.53
(2H, m), 7.45-7.42 (2H, m), 7.03 (1H, t, J=7.8 Hz), 6.92 (2H, t,
J=8.4 Hz), 6.00-5.84 (1H, m), 5.21-5.09 (2H, m) 4.81 (2H, dt,
J=47.4, 4.2 Hz), 4.32 (2H, dt, J=23.1, 4.2 Hz), 4.14 (2H, t, J=7.2
Hz), 3.90 (3H, s), 3.43 (2H, t, J=7.5 Hz), 3.00 (2H, t, J=7.5 Hz),
2.64-2.61 (2H, m)
Example 277
Using the compound obtained in Example 271 and isobutyl bromide,
white powdery
1-[2-(2-fluoroethoxy)phenyl]-3-[2-(3-isobutoxy-4-methoxyphenyl)ox-
azol-4-yl]propan-1-one was obtained following the procedure of
Example 3.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.73 (1H, dd, J=7.8, 18 Hz),
7.57-7.51 (2H, m), 7.48-7.42 (2H, m), 7.40 (1H, t, J=7.5 Hz), 6.92
(2H, t, J=8.7 Hz), 4.81 (2H, dt, J=47.4, 4.2 Hz), 4.32 (2H, dt,
J=23.1, 4.2 Hz), 3.90 (3H, s), 3.84 (2H, d, J=6.9 Hz), 3.43 (2H, t,
J=7.5 Hz), 3.00 (2H, t, J=7.5 Hz), 2.23-2.14 (1H, m), 1.04 (6H, d,
J=5.7 Hz)
Example 278
Using the compound obtained in Example 272 and 2-bromopropane,
white powdery
1-[2-(2,2-difluoroethoxy)phenyl]-3-[2-(3-isopropoxy-4-methoxyphen-
yl)oxazol-4-yl]propan-1-one was obtained following the procedure of
Example 3.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.74 (1H, dd, J=7.5, 1.8 Hz),
7.59-7.44 (3H, m), 7.41 (1H, s), 7.08 (1H, t, J=7.5 Hz), 6.91 (1H,
d, J=8.4 Hz), 6.22 (1H, tt, J=54.6, 3.9 Hz) 4.65 (1H, sept., J=6.0
Hz), 4.29 (2H, td, J=12.9, 3.9 Hz), 3.90 (3H, s) 3.38 (2H, t, J=7.5
Hz) 2.99 (2H, t, J=7.5 Hz) 1.40 (6H, d, J=6.0 Hz)
Example 279
Using the compound obtained in Example 272 and 1-bromopropane,
white powdery
1-[2-(2,2-difluoroethoxy)phenyl]-3-[2-(3-propoxy-4-methoxyphenyl)-
oxazol-4-yl]propan-1-one was obtained following the procedure of
Example 3.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.74 (1H, dd, J=7.8, 1.8 Hz),
7.61-7.43 (3H, m), 7.41 (1H, s), 7.08 (1H, t, J=7.5 Hz), 6.92-6.89
(2H, m), 6.23 (1H, tt, J=54.6, 3.9 Hz), 4.29 (2H, td, J=12.9, 3.9
Hz), 4.06 (2H, t, J=6.9 Hz), 3.91 (3H, s), 3.38 (2H, t, J=1.5 Hz),
2.99 (2H, t, J=7.5 Hz), 1.90 (2H, qt, J=7.2 Hz), 1.06 (3H, t, J=7.2
Hz)
Example 280
Using the compound obtained in Example 272 and ethyl iodide, white
powdery
1-[2-(2,2-difluoroethoxy)phenyl]-3-[2-(3-ethoxy-4-methoxyphenyl)o-
xazol-4-yl]propan-1-one was obtained following the procedure of
Example 3.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.74 (1H, dd, J=7.8, 1.8 Hz),
7.61-7.44 (3H, m), 7.41 (1H, s), 7.08 (1H, t, J=7.8 Hz), 6.93-6.90
(2H, m), 6.23 (1H, tt, J=54.6, 3.9 Hz) 4.29 (2H, td, J=12.9, 3.9
Hz), 4.18 (2H, q, J=6.9 Hz), 3.92 (3H, s), 3.38 (2H, t, J=7.5 Hz),
2.99 (2H, t, J=7.5 Hz), 1.50 (3H, t, J=6.9 Hz)
Example 281
Using the compound obtained in Example 272 and ally bromide, white
powdery
3-[2-(3-allyloxy-4-methoxyphenyl)oxazol-4-yl]-1-[2-(2,2-difluoroe-
thoxy)phenyl]propan-1-one was obtained following the procedure of
Example 3.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.74 (1H, dd, J=7.8, 1.8 Hz),
7.60-7.44 (3H, m), 7.41 (1H, s), 7.08 (1H, t, J=7.5 Hz), 6.94-6.89
(2H, m), 6.41-6.04 (2H, m), 5.44 (1H, dd, J=17.4, 1.5 Hz), 5.31
(1H, dd, J=10.2, 1.5 Hz), 4.29 (2H, td, J=12.9, 3.9 Hz), 3.92 (3H,
s), 3.38 (2H, t, J=7.2 Hz), 2.99 (2H, t, J=7.2 Hz)
Example 282
Using the compound obtained in Example 272 and 4-bromo-1-butene,
white powdery
3-[2-(3-but-3-enyloxy-4-methoxyphenyl)oxazol-4-yl]-1-[2-(2,2-difl-
uoroethoxy)phenyl]propan-1-one was obtained following the procedure
of Example 3.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.75 (1H, dd, J=7.8, 1.8 Hz),
7.60-7.44 (3H, m), 7.42 (1H, s), 7.09 (1H, t, J=7.5 Hz), 6.93-6.89
(2H, m), 6.23 (1H, tt, J=54.6, 3.9 Hz), 5.99-5.85 (1H, m),
5.23-5.10 (2H, m), 4.29 (2H, td, J=12.9, 3.9 Hz), 4.14 (2H, t,
J=7.2 Hz), 3.91 (3H, s), 3.39 (2H, t, J=7.2 Hz), 2.99 (2H, t, J=7.2
Hz), 2.68-2.60 (2H, m)
Example 283
Using the compound obtained in Example 272 and
(bromomethyl)cyclopropane, white powdery 3-[2-(3-cyclopropyl
methoxy-4-methoxyphenyl)oxazol-4-yl]-1-[2-(2,2-difluoroethoxy)phenyl]prop-
an-1-one was obtained following the procedure of Example 3.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.75 (1H, dd, J=7.8, 1.8 Hz),
7.58-7.44 (3H, m), 7.41 (1H, s), 7.09 (1H, t, J=7.5 Hz), 6.93-6.90
(2H, m), 6.24 (1H, tt, J=54.6, 3.9 Hz), 4.29 (2H, td, J=12.9, 3.9
Hz), 3.94-3.91 (5H, m), 3.39 (2H, t, J=7.2 Hz), 2.99 (2H, t, J=7.2
Hz), 1.43-1.33 (1H, m), 0.70-0.63 (2H, m), 0.41-0.35 (2H, m)
Example 284
Using the compound obtained in Example 272 and the compound
obtained in Reference Example 85, white powdery
3-{2-[3-(2,2-difluoroethoxy)-4-methoxyphenyl]oxazol-4-yl}-1-[2-(2,2-diflu-
oroethoxy)phenyl]propan-1-one was obtained following the procedure
of Example 3.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.74 (1H, dd, J=7.8, 1.8 Hz),
7.65 (1H, dd, J=7.8, 1.8 Hz), 7.50 (1H, d, J=2.1 Hz), 7.50-7.42
(1H, m), 7.42 (1H, s), 7.08 (1H, t, J=7.5 Hz), 6.96-6.89 (2H, m),
6.42-5.95 (2H, m), 4.35-4.23 (4H, m), 3.92 (3H, s), 3.39 (2H, t,
J=7.5 Hz), 3.00 (2H, t, J=7.5 Hz)
Example 285
Using the compound obtained in Example 272 and isobutyl bromide,
white powdery
1-[2-(2,2-difluoroethoxy)phenyl]-3-[2-(3-isobutoxy-4-methoxypheny-
l)oxazol-4-yl]-propan-1-one was obtained following the procedure of
Example 3.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.74 (1H, d, J=7.5 Hz), 7.57-7.44
(3H, m), 7.41 (1H, s), 7.08 (1H, t, J=7.5 Hz), 6.92-6.89 (2H, m),
6.23 (1H, tt, J=54.6, 3.9 Hz), 4.29 (2H, td, J=12.9, 3.9 Hz), 3.90
(3H, s), 3.85 (2H, d, J=6.6 Hz), 3.38 (2H, t, J=7.5 Hz), 2.99 (2H,
t, J=7.5 Hz), 2.19 (1H, qt, J=6.6 Hz), 1.05 (6H, d, J=6.6 Hz)
Example 286
Using the compound obtained in Reference Example 35 and the
compound obtained in Reference Example 70, pale yellow oily
3-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-1-(2methoxymethoxyphenyl)propan-1-o-
ne was obtained following the procedure of Example 190.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.66 (1H, dd, J=7.8, 1.8 Hz),
7.56-7.38 (3H, m), 7.17 (1H, d, J=8.4 Hz), 7.04 (1H, t, J=7.5 Hz),
6.92-6.88 (2H, m), 5.26 (2H, s), 4.21-4.08 (4H, m), 3.49 (3H, s),
3.40 (2H, t, J=7.2 Hz), 3.00 (2H, t, J=7.2 Hz), 1.51-1.45 (6H,
m)
Example 287
Using the compound obtained in Example 286, white powdery
3-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-1-(2-hydroxyphenyl)propan-1-one
was obtained following the procedure of Example 266.
.sup.1H-NMR (CDCl.sub.3) .delta.: 12.25 (1H, s), 7.82 (1H, dd,
J=8.1, 1.5 Hz), 7.60-7.43 (4H, m), 6.98 (1H, d, J=8.4 Hz),
6.92-6.86 (2H, m), 4.21-4.10 (4H, m), 3.44 (2H, t, J=7.2 Hz), 3.03
(2H, t, J=7.2 Hz), 1.51-1.43 (6H, m)
Example 288
Using the compound obtained in Example 287 and
chlorodifluoromethane, white powdery 3-[2-(3,4-diethoxyphenyl
oxazol-4-yl)-1-(2-difluoromethoxyphenyl)propan-1-one was obtained
following the procedure of Example 19.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.51 (1H, d, J=8.7 Hz), 7.60-7.45
(3H, m), 7.30 (1H, s), 7.28-7.19 (2H, m), 6.90 (1H, d, J=8.7 Hz),
6.58 (1H, t, J=75 Hz), 4.15 (4H, q, J=7.2 Hz) 3.36 (2H, t, J=7.2
Hz), 3.00 (2H, t, J=7.2 Hz), 1.47 (6H, t, J=7.2 Hz)
Example 289
Using the compound obtained in Example 287 and the compound
obtained in Reference Example 84, white powdery
3-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-1-[2-(2-fluoroethoxy)phenyl]propan--
1-one was obtained following the procedure of Example 3.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.74 (1H, dd, J=7.8, 1.8 Hz),
7.56-7.41 (4H, m), 7.04 (1H, td, J=7.5, 0.9 Hz), 6.95-6.88 (2H, m),
4.81 (2H, dt, J=47.1, 4.2 Hz), 4.32 (2H, dt, J=27.3, 4.2 Hz),
4.21-4.10 (4H, m), 3.43 (2H, t, J=7.2 Hz) 3.00 (2H, t, J=7.2 Hz)
1.50-1.45 (6H, m)
Example 290
Using the compound obtained in Example 287 and the compound
obtained in Reference Example 85, white powdery
3-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-1-[2-(2,2-difluoroethoxy)phenyl]pro-
pan-1-one was obtained following the procedure of Example 3.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.74 (1H, dd, J=7.5, 1.8 Hz),
7.56-7.43 (3H, m), 7.41 (1H, s), 7.08 (1H, t, J=7.5 Hz), 6.90 (1H,
d, J=7.8 Hz), 6.23 (1H, tt, J=54.9, 3.9 Hz), 4.29 (2H, td, J=13.2,
3.9 Hz), 4.21-4.10 (4H, m), 3.38 (2H, t, J=7.5 Hz) 2.98 (2H, t,
J=7.5 Hz), 1.50-1.45 (6H, m)
Example 291
A 0.2 g quantity of the compound obtained in Example 223 and 0.1 ml
of triethylamine were dissolved in 5 ml of dichloromethane, 0.1 ml
of acetyl chloride was added to the obtained solution, and the
mixture was stirred for 6 hours at room temperature. At the
completion of the reaction, water was added to the reaction
mixture, and the obtained mixture was extracted with ethyl acetate.
The organic layer was washed twice with water, and the solvent was
distilled off. The residue was purified using a silica gel column
(n-hexane:ethyl acetate=2:1), and the obtained crude crystals were
recrystallized with ethanol, thereby yielding 15 mg of white
powdery
2-{3-[2-(3-isopropoxy-4-methoxyphenyl)oxazol-4-yl]propionyl}phenyl
acetate.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.83 (1H, dd, J=7.8, 1.5 Hz),
7.60-7.50 (3H, m), 7.42 (1H, s), 7.34-7.28 (1H, m), 7.12 (1H, dd,
J=8.1, 0.9 Hz), 6.92 (1H, d, J=8.4 Hz), 4.69-4.61 (1H, m), 3.90
(3H, s), 3.32 (2H, t, J=7.2 Hz), 2.97 (2H, t, J=7.2 Hz), 2.35 (3H,
s), 1.40 (6H, d, J=6.0 Hz)
Example 292
Using the compound obtained in Reference Example 35 and
1-(2-trifluoromethoxyphenyl)ethanone, white powdery
3-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-1-(2-trifluoromethoxyphenyl)propan--
1-one was obtained following the procedure of Example 190.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.70 (1H, dd, J=7.8, 1.8 Hz),
7.58-7.41 (3H, m), 7.38 (1H, s), 7.35-7.29 (2H, m), 6.90 (1H, d,
J=8.4 Hz), 4.20-4.10 (4H, m), 3.34 (2H, t, J=6.9 Hz), 3.00 (2H, t,
J=6.9 Hz), 1.48 (6H, t, J=6.9 Hz)
Example 293
Using the compound obtained in Reference Example 11 and
1-(2-trifluoromethoxyphenyl)ethanone, white powdery
3-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-trifluoro
methoxyphenyl)propan-1-one was obtained following the procedure of
Example 190.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.70 (1H, d, J=8.7 Hz), 7.57-7.53
(3H, m), 7.49 (1H, s), 7.42-7.30 (2H, m), 6.90 (1H, d, J=8.7 Hz),
3.94-3.91 (5H, m), 3.34 (2H, t, J=7.2 Hz) 3.00 (2H, t, J=7.2 Hz),
1.42-1.30 (1H, m), 0.67-0.64 (2H, m), 0.40-0.36 (2H, m)
Using the compound obtained in Reference Example 35 and the
corresponding acetophenone derivatives, compounds of Examples 294
to 299 were obtained following the procedure of Example 190.
Example 294
3-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-1-(2,5-dimethoxyphenyl)propan-1-one
White Powder
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.57-7.52 (2H, m), 7.40 (1H, s),
7.01 (1H, dd, J=9.0, 3.3 Hz), 6.90 (2H, t, J=8.4 Hz), 4.20-4.10
(4H, m), 3.85 (3H, s), 3.78 (3H, s), 3.39 (2H, t, J=7.2 Hz), 2.98
(2H, t, J=7.2 Hz), 1.47 (6H, t, J=6.9 Hz)
Example 295
3-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-1-(2-ethoxy-5-methylphenyl)propan-1--
one
White Powder
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.61-7.49 (3H, m), 7.40 (1H, s),
7.25-7.20 (2H, m), 6.90 (1H, d, J=8.1 Hz), 6.83 (1H, d, J=8.4 Hz),
4.21-4.06 (6H, m), 3.41 (2H, t, J=7.5 Hz), 2.99 (2H, t, J=7.5 Hz),
2.28 (3H, s), 1.53-1.40 (9H, m)
Example 296
3-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-1-(2,4-dimethylphenyl)propan-1-one
Colorless Powder
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.63 (1H, d, J=8.4 Hz), 7.54 (1H,
dd, J=8.4, 1.8 Hz), 7.51 (1H, d, J=1.8 Hz), 7.42 (1H, s), 7.06-7.02
(2H, m), 6.90 (1H, d, J=8.4 Hz), 4.17 (2H, q, J=6.9 Hz), 4.14 (2H,
q, J=6.9 Hz), 3.30 (2H, t, J=7.2 Hz), 2.99 (2H, t, J=7.2 Hz), 2.49
(3H, s), 2.34 (3H, s), 1.48 (6H, t, J=6.9 Hz)
Example 297
3-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-1-(2,5-dimethylphenyl)propan-1-one
Colorless Needle Crystals
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.55 (1H, br s, J=8.7 Hz), 7.52
(1H, br s), 7.44 (1H, br d, J=8.7 Hz), 7.17-7.09 (2H, m), 6.90 (1H,
d, J=8.7 Hz), 4.17 (2H, q, J=6.9 Hz), 4.14 (2H, q, J=6.9 Hz), 3.29
(2H, t, J=7.2 Hz), 2.99 (2H, t, J=7.2 Hz), 2.44 (3H, s), 2.33 (3H,
s), 1.47 (6H, t, J=6.9 Hz)
Example 298
3-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-1-(2-ethoxy-4-methylphenyl)propan-1--
one
White Powder
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.66 (1H, d, J=7.8 Hz), 7.60-7.51
(2H, m), 7.39 (1H, s), 6.90 (1H, d, J=8.4 Hz), 6.79 (1H, d, J=8.4
Hz), 6.73 (1H, s), 4.21-4.08 (6H, m), 3.40 (2H, t, J=7.2 Hz), 2.98
(2H, t, J=7.2 Hz), 2.36 (3H, s), 1.53-1.45 (9H, m)
Example 299
3-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-1-(2-ethoxy-4-fluorophenyl)propan-1--
one
Colorless Needle Crystals
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.78 (1H, dd, J=8.7, 7.2 Hz),
7.54 (1H, dd, J=8.4, 2.1 Hz), 7.51 (1H, d, J=2.1 Hz), 7.39 (1H, br
s), 6.90 (1H, d, J=8.4 Hz), 6.71-6.61 (2H, m), 4.16 (2H, q, J=6.9
Hz), 4.14 (2H, q, J=6.9 Hz), 4.11 (2H, q, J=6.9 Hz), 3.39 (2H, t,
J=7.2 Hz), 2.98 (2H, t, J=7.2 Hz), 1.49 (3H, t, J=6.9 Hz), 1.47
(6H, t, J=6.9 Hz)
Example 300
The compound obtained in Reference Example 54 and methyl
(2-methoxymethyl)benzoate were used and treated following the
procedure of Example 100, followed by treatment according to
Reference Example 48, yielding white powdery 3-[2-(3,4-diethoxy
phenyl)oxazol-4-yl]-1-(2-methoxymethylphenyl)propan-1-one.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.74 (1H, dd, J=7.8, 1.2 Hz),
7.64-7.27 (6H, m), 6.91 (1H, d, J=8.4 Hz), 4.73 (2H, s), 4.21-4.10
(4H, m), 3.43 (3H, s), 3.34 (2H, t, J=7.2 Hz), 3.00 (2H, t, J=7.2
Hz), 1.51-1.43 (6H, m)
Using the compound obtained in Reference Example 54 and the
corresponding methyl benzoate derivatives, compounds of Examples
301 to 303 were obtained following the procedure of the Example
300.
Example 301
3-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-1-(2-ethylphenyl)propan-1-one
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.62-7.51 (4H, m), 7.43 (1H, s),
7.38-7.30 (2H, m), 6.90 (1H, d, J=8.7 Hz), 4.18-4.13 (4H, m), 3.31
(2H, t, J=7.2 Hz), 3.00 (2H, t, J=7.2 Hz), 2.81 (2H, q, J=7.5 Hz),
1.48 (6H, t, J=6.9 Hz), 1.20 (3H, t, J=7.5 Hz)
Example 302
3-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-1-(2,3-dimethoxyphenyl)propan-1-one
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.56-7.51 (2H, m), 7.41 (1H, s),
7.18-7.01 (3H, m), 6.90 (1H, d, J=8.4 Hz), 4.21-4.10 (4H, m), 3.89
(6H, s), 3.38 (2H, t, J=7.2 Hz), 2.99 (2H, t, J=7.2 Hz), 1.48 (6H,
t, J=6.9 Hz)
Example 303
3-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-1-(2-ethoxy-3-methylphenyl)propan-1--
one
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.55-7.51 (2H, m), 7.40 (1H, s),
7.36-7.29 (2H, m), 7.04 (1H, t, J=7.2 Hz), 6.90 (1H, d, J=8.1 Hz),
4.20-4.11 (4H, m), 3.83 (2H, q, J=7.5 Hz), 3.39 (2H, t, J=7.2 Hz),
2.98 (2H, t, J=7.2 Hz), 2.30 (3H, s), 1.48 (6H, t, J=6.9 Hz), 1.26
(3H, t, J=6.9 Hz)
Example 304
Using the compound obtained in Reference Example 58 and
1-(2-ethoxy-4-fluorophenyl)ethanone, pale yellow powdery
1-(2-ethoxy-4-fluorophenyl)-3-[2-(3-ethoxy-4-methoxyphenyl)oxazol-4-yl]pr-
opan-1-one was obtained following the procedure of Example 190.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.77 (1H, t, J=7.8 Hz), 7.56 (1H,
dd, J=8.4, 1.8 Hz), 7.51 (1H, d, J=1.8 Hz), 7.40 (1H, s), 6.91 (1H,
d, J=8.4 Hz), 6.71-6.61 (2H, m), 4.21-4.07 (4H, m), 3.92 (3H, s),
3.39 (2H, t, J=7.2 Hz), 2.98 (2H, t, J=7.2 Hz), 1.52-1.47 (6H,
m)
Example 305
Using the compound obtained in Reference Example 58 and
1-(4-fluoro-2-isopropoxyphenyl)ethanone, colorless oily
3-[2-(3-ethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(4-fluoro-2-isopropoxy
phenyl)propan-1-one was obtained following the procedure of Example
190.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.77 (1H, t, J=7.8 Hz), 7.57 (1H,
dd, J=8.4, 1.8 Hz), 7.51 (1H, d, J=1.8 Hz), 7.40 (1H, s), 6.91 (1H,
d, J=8.4 Hz), 6.71-6.61 (2H, m), 4.63 (1H, sept, J=6.0 Hz), 4.18
(2H, q, J=6.9 Hz), 3.92 (3H, s), 3.38 (2H, t, J=7.2 Hz), 2.98 (2H,
t, J=7.2 Hz), 1.50 (3H, t, J=6.9 Hz), 1.42 (6H, d, J=6.0 Hz)
Example 306
Using the compound obtained in Reference Example 68 and
1-(2-ethoxy-5-methylphenyl)ethanone, white powdery
1-(2-ethoxy-5-methylphenyl)-3-[2-(3-isopropoxy-4-methoxyphenyl)oxazol-4-y-
l]propan-1-one was obtained following the procedure of Example
190.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.60-7.40 (3H, m), 7.39 (1H, s),
7.24-7.19 (1H, m), 6.91 (1H, d, J=8.1 Hz), 6.83 (1H, d, J=8.4 Hz),
4.69-4.58 (1H, m), 4.10 (2H, q, J=6.9 Hz), 3.89 (3H, s), 3.41 (2H,
t, J=7.2 Hz), 2.98 (2H, t, J=7.2 Hz), 2.29 (3H, s), 1.48-1.38 (9H,
m)
Example 307
Using the compound obtained in Reference Example 68 and
1-(2-ethoxy-4-methylphenyl)ethanone, white powdery
1-(2-ethoxy-4-methylphenyl)-3-[2-(3-isopropoxy-4-methoxyphenyl)oxazol-4-y-
l]propan-1-one was obtained following the procedure of Example
190.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.66 (1H, d, J=8.1 Hz), 7.59-7.53
(2H, m), 7.39 (1H, s), 6.91 (1H, d, J=8.4 Hz), 6.79 (1H, d, J=8.1
Hz), 6.73 (1H, s), 4.58-4.71 (1H, m), 4.12 (2H, q, J=6.9 Hz), 3.90
(1H, s) 3.40 (2H, t, J=7.5 Hz), 2.98 (2H, t, J=7.5 Hz), 2.36 (3H,
s), 1.48 (3H, t, J=6.9 Hz), 1.40 (6H, d, J=6.0 Hz)
Example 308
Using the compound obtained in Example 136 and
chlorodifluoromethane, white powdery
3-[2-(3-difluoromethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-
-yl)propan-1-one was obtained following the procedure of Example
4.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.50 (1H, m), 7.83 (1H, dd,
J=8.4, 2.1 Hz), 7.78 (1H, d, J=2.1 Hz), 7.58 (1H, d, J=7.8 Hz),
7.47 (1H, s), 7.32 (1H, m), 7.00 (1H, d, J=8.4 Hz), 6.58 (1H, t,
J=74.7 Hz), 3.93 (3H, s), 3.59 (2H, t, J=7.2 Hz), 3.00 (2H, t,
J=7.2 Hz), 2.57 (3H, s)
Example 309
Using the compound obtained in Example 136 and the compound
obtained in Reference Example 85, white powdery
3-{2-[3-(2,2-difluoroethoxy)-4-methoxyphenyl]oxazol-4-yl}-1-(3-methyl
pyridin-2-yl)propan-1-one was obtained following the procedure of
Example 3.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.50 (1H, dd, J=4.5, 0.9 Hz),
7.66 (1H, dd, J=8.4, 2.1 Hz), 7.60-7.54 (2H, m), 7.46 (1H, s),
7.35-7.31 (1H, m), 6.94 (1H, d, J=8.7 Hz), 6.16 (1H, tt, J=54.9,
1.2 Hz) 4.29 (2H, td, J=12.9, 1.2 Hz), 3.92 (3H, s), 3.61 (2H, t,
J=6.9 Hz), 3.01 (2H, t, J=6.9 Hz), 2.58 (3H, s)
Example 310
Using the compound obtained in Example 136 and the compound
obtained in Reference Example 84, white powdery
3-{2-[3-(2-fluoroethoxy)-4-methoxyphenyl]oxazol-4-yl}-1-(3-methylpyridin--
2-yl)propan-1-one was obtained following the procedure of Example
3.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.50-8.49 (1H, m), 7.63-7.54 (3H,
m), 7.45 (1H, s), 7.34-7.27 (1H, m), 6.93 (1H, d, J=8.7 Hz), 4.88
(1H, t, J=4.2 Hz), 4.72 (1H, t, J=4.2 Hz) 4.39 (1H, t, J=4.2 Hz),
4.30 (1H, t, J=4.2 Hz), 3.92 (3H, s), 3.60 (2H, t, J=7.2 Hz), 3.00
(2H, t, J=7.2 Hz), 2.57 (3H, s)
Example 311
Using the compound obtained in Example 136 and 2-bromobutane,
yellow oily
3-[2-(3-sec-butoxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)p-
ropan-1-one was obtained following the procedure of Example 3.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.50 (1H, dd, J=4.5, 1.2 Hz),
7.59-7.55 (3H, m), 7.54 (1H, s), 7.45-7.30 (1H, m), 6.91 (1H, d,
J=8.4 Hz), 4.43-4.37 (1H, m), 3.89 (3H, s), 3.60 (2H, t, J=7.5 Hz),
3.01 (2H, t, J=7.5 Hz), 2.57 (3H, s), 1.86-1.62 (2H, m), 1.34 (3H,
d, J=6.6 Hz), 1.00 (3H, t, J=6.6 Hz)
Example 312
Using the compound obtained in Example 136 and 3-bromopentane,
white powdery 3-{2-[3-(1-ethylpropoxy)-4-methoxy
phenyl]oxazol-4-yl}-1-(3-methylpyridin-2-yl)propan-1-one was
obtained following the procedure of Example 3.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.50 (1H, dd, J=4.5, 1.2 Hz),
7.61-7.53 (3H, m), 7.45 (1H, s), 7.34-7.30 (1H, m), 6.91 (1H, d,
J=8.1 Hz), 4.28-4.20 (1H, m), 3.89 (3H, s), 3.60 (2H, t, J=7.5 Hz),
3.01 (2H, t, J=7.5 Hz), 2.57 (3H, s), 1.78-1.68 (4H, m), 0.98 (6H,
t, J=6.6 Hz)
Example 313
Using the compound obtained in Example 101 and
chlorodifluoromethane, white powdery
3-[2-(3-difluoromethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)pr-
opan-1-one was obtained following the procedure of Example 4.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.85-7.80 (2H, m), 7.70 (1H, m),
7.50-7.40 (2H, m), 7.0-6.9 (3H, m), 6.58 (1H, t, J=74.4 Hz), 4.14
(2H, q, J=6.9 Hz), 3.93 (3H, s), 3.42 (2H, t, J=7.2 Hz), 2.99 (2H,
t, J=7.2 Hz), 1.48 (3H, t, J=6.9 Hz)
Example 314
Using the compound obtained in Example 101 and the compound
obtained in Reference Example 85, white powdery
3-{2-[3-(2,2-difluoroethoxy)-4-methoxyphenyl]oxazol-4-yl}-1-(2-ethoxy
phenyl)propan-1-one was obtained following the procedure of Example
3.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.73-7.63 (2H, m), 7.55 (1H, d,
J=2.1 Hz), 7.46-7.39 (2H, m), 7.01-6.91 (3H, m), 6.16 (1H, tt,
J=54.9, 1.2 Hz), 4.29 (2H, td, J=12.9, 1.2 Hz), 4.14 (2H, q, J=6.9
Hz), 3.91 (3H, s), 3.43 (2H, t, J=7.2 Hz), 3.00 (2H, t, J=7.2 Hz),
1.48 (3H, t, J=7.2 Hz)
Example 315
Using the compound obtained in Example 101 and the compound
obtained in Reference Example 84, white powdery
1-(2-ethoxyphenyl)-3-{2-[3-(2-fluoroethoxy)-4-methoxyphenyl]oxazol-4-yl}p-
ropan-1-one was obtained following the procedure of Example 3.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.69 (1H, dd, J=7.8, 1.8 Hz),
7.61 (1H, dd, J=8.4, 1.8 Hz), 7.55 (1H, s), 7.44-7.39 (2H, m),
7.00-6.91 (3H, m), 4.81 (2H, dt, J=47.4, 4.2 Hz), 4.32 (2H, dt,
J=23.1, 4.2 Hz), 4.17-4.10 (2H, m), 3.90 (3H, s), 3.41 (2H, t,
J=7.2 Hz), 2.99 (2H, t, J=7.2 Hz), 1.46 (3H, t, J=5.7 Hz)
Reference Example 86
Using the compound obtained in Reference Example 59 and the
compound obtained in Reference Example 85, white powdery ethyl
4-benzyloxy-3-(2,2-difluoroethoxy)benzoate was obtained following
the procedure of Example 4.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.71 (1H, dd, J=8.4, 2.1 Hz),
7.61 (1H, d, J=2.1 Hz), 7.44-7.29 (5H, m), 6.95 (1H, d, J=8.4 Hz),
6.11 (1H, tt, J=54.9, 4.2 Hz), 5.19 (2H, s), 4.38-4.21 (4H, m),
1.39 (3H, t, J=7.2 Hz)
Reference Example 87
Using the compound obtained in Reference Example 86, white powdery
4-benzyloxy-3-(2,2-difluoroethoxy)benzoic acid was obtained
following the procedure of Reference Example 3.
.sup.1H-NMR (DMSO d.sub.6) .delta.: 7.61 (1H, dd, J=8.4, 1.8 Hz),
7.54 (1H, d, J=1.8 Hz), 7.50-7.30 (5H, m), 7.18 (1H, d, J=8.4 Hz),
6.38 (1H, tt, J=54.3, 3.6 Hz), 5.22 (2H, s), 4.37 (2H, td, J=14.7,
3.6 Hz)
Reference Example 88
Using the compound obtained in Reference Example 87, white powdery
4-benzyloxy-3-(2,2-difluoroethoxy)benzamide was obtained following
the procedure of Reference Example 4.
.sup.1H-NMR (DMSO d.sub.6) .delta.: 7.86 (1H, br s), 7.56-7.29 (7H,
m), 7.25 (1H, br s), 7.14 (1H, d, J=8.4 Hz), 6.40 (1H, tt, J=54.3,
3.6 Hz), 5.20 (2H, s), 4.34 (2H, td, J=14.7, 3.6 Hz)
Reference Example 89
Using the compound obtained in Reference Example 88, white powdery
2-[4-benzyloxy-3-(2,2-difluoroethoxy)phenyl]-4-chloromethyloxazole
was obtained following the procedure of Reference Example 5.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.68-7.60 (3H, m), 7.45-7.30 (5H,
m), 7.01 (1H, d, J=8.4 Hz), 6.12 (1H, tt, J=54.9, 4.2 Hz) 5.18 (2H,
s), 4.56 (2H, s), 4.30 (2H, td, J=13.2, 4.2 Hz)
Reference Example 90
Using the compound obtained in Reference Example 89, white powdery
dimethyl
2-{2-[4-benzyloxy-3-(2,2-difluoroethoxy)phenyl]oxazol-4-ylmethyl-
}malonate was obtained following the procedure of Reference Example
47.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.63-7.57 (2H, m), 7.45-7.30 (6H,
m), 6.99 (1H, d, J=8.1 Hz), 6.12 (1H, tt, J=54.9, 4.2 Hz), 5.18
(2H, s), 4.29 (2H, td, J=13.2, 4.2 Hz), 3.89 (2H, t, J=7.5 Hz),
3.75 (6H, s), 3.18 (2H, t, J=7.5 Hz)
Reference Example 91
Using the compound obtained in Reference Example 90, brownish oily
methyl 3-{2-[4-benzyloxy-3-(2,2-difluoro
ethoxy)phenyl]oxazol-4-yl}-propionate was obtained following the
procedure of Reference Example 48.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.64-7.59 (2H, m), 7.42-7.33 (6H,
m), 6.99 (1H, d, J=8.1 Hz), 6.12 (1H, tt, J=54.9, 4.2 Hz), 5.18
(2H, s), 4.29 (2H, td, J=13.2, 4.2 Hz), 3.68 (3H, s), 2.91 (2H, t,
J=7.5 Hz), 2.72 (2H, t, J=7.5 Hz)
Example 316
Using the compound obtained in Reference Example 91, pale yellow
oily methyl
2-{2-[4-benzyloxy-3-(2,2-difluoroethoxy)-phenyl]oxazol-4-ylmethyl}-
-3-(3-methylpyridin-2-yl)-3-oxopropionate was obtained following
the procedure of Example 100.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.50 (1H, d, J=4.5 Hz), 7.60-7.52
(3H, m), 7.46-7.30 (7H, m), 6.97 (1H, d, J=8.1 Hz), 6.11 (1H, tt,
J=54.9, 4.2 Hz), 5.24-5.16 (3H, m), 4.27 (2H, td, J=13.2, 4.2 Hz),
3.66 (3H, s), 3.34-3.22 (2H, m), 2.60 (3H, s)
Example 317
Using the compound obtained in Example 316, white powdery
3-{2-[3-(2,2-difluoroethoxy)-4-hydroxyphenyl]oxazol-4-yl}-1-(3-methylpyri-
din-2-yl)propan-1-one was obtained following the procedure of
Example 136.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.50 (1H, d, J=4.5 Hz), 7.61-7.57
(2H, m), 7.52 (1H, s), 7.45 (1H, s), 7.34-7.30 (1H, m), 7.00 (1H,
d, J=8.1 Hz), 6.11 (1H, tt, J=54.9, 4.2 Hz), 6.07 (1H, s), 4.32
(2H, td, J=13.2, 4.2 Hz), 3.59 (2H, t, J=7.5 Hz), 3.00 (2H, t,
J=7.5 Hz), 2.57 (3H, s)
Example 318
Using the compound obtained in Example 317 and methyl iodide, white
powdery
3-{2-[3-(2,2-difluoroethoxy)-4-ethoxyphenyl]oxazol-4-yl}-1-(3-met-
hylpyridin-2-yl)-propan-1-one was obtained following the procedure
of Example 3.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.51 (1H, d, J=4.5 Hz), 7.66-7.57
(3H, m), 7.46 (1H, s), 7.34-7.30 (1H, m), 6.94 (1H, d, J=8.4 Hz),
6.14 (1H, tt, J=54.6, 3.9 Hz), 4.28 (2H, td, J=12.9, 3.9 Hz), 4.13
(2H, q, J=6.9 Hz), 3.60 (2H, t, J=7.5 Hz), 3.02 (2H, t, J=7.5 Hz),
2.57 (3H, s), 1.47 (3H, t, J=6.9 Hz)
Example 319
Using the compound obtained in Example 317 and 2-bromopropane,
white powdery
3-{2-[3-(2,2-difluoroethoxy)-4-isopropoxyphenyl]oxazol-4-yl}-1-(3-
-methylpyridin-2-yl)propan-1-one was obtained following the
procedure of Example 3.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.51 (1H, d, J=4.5 Hz), 7.65-7.57
(3H, m), 7.46 (1H, s), 7.34-7.30 (1H, m), 6.95 (1H, d, J=8.4 Hz),
6.12 (1H, tt, J=54.6, 3.9 Hz), 4.62-4.54 (1H, m), 4.26 (2H, td,
J=12.9, 3.9 Hz), 3.60 (2H, t, J=7.5 Hz), 3.01 (2H, t, J=7.5 Hz),
2.57 (3H, s), 1.37 (6H, d, J=6.0 Hz)
Example 320
Using the compound obtained in Reference Example 7 and
2-difluoromethoxy benzoic acid, white powdery
N-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-difluoromethoxyben-
zamide was obtained following the procedure of Example 1.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.10 (1H, dd, J=7.8, 1.8 Hz),
7.64-7.57 (3H, m), 7.51-7.45 (4H, m), 7.40-7.26 (4H, m), 7.15 (1H,
d, J=8.4 Hz), 6.95 (1H, d, J=9.0 Hz), 6.59 (1H, t, J=72.9 Hz), 5.20
(2H, s), 4.61 (2H, d, J=5.4 Hz), 3.93 (3H, s)
Example 321
Using the compound obtained in Example 320, white powdery
2-difluoromethoxy-N-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-ylmethyl]-benz-
amide was obtained following the procedure of Example 2.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.09 (1H, d, J=7.8 Hz), 7.64-7.45
(5H, m), 7.32 (1H, t, J=7.8 Hz), 7.15 (1H, d, J=7.8 Hz), 6.91 (1H,
d, J=8.4 Hz), 6.60 (1H, t, J=72.9 Hz), 5.77 (1H, s), 4.61 (2H, d,
J=5.1 Hz), 3.94 (3H, s)
Example 322
Using the compound obtained in Example 321 and allyl bromide, white
powdery
N-[2-(3-allyloxy-4-methoxyphenyl)-oxazol-4-ylmethyl]-2-difluorome-
thoxybenzamide was obtained following the procedure of Example
3.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.10 (1H, d, J=7.8 Hz), 7.64-7.30
(6H, m), 7.15 (1H, d, J=8.4 Hz), 6.94 (1H, d, J=8.1 Hz), 6.61 (1H,
t, J=75 Hz), 6.17-6.08 (1H, m), 5.45 (1H, dd, J=17.1, 1.5 Hz), 5.32
(1H, dd, J=10.5, 1.5 Hz), 4.70 (2H, t, J=5.4 Hz), 4.62 (2H, t,
J=5.4 Hz), 3.93 (3H, s)
Example 323
Using the compound obtained in Example 321 and 2-bromopropane,
white powdery
2-difluoromethoxy-N-[2-(3-isopropoxy-4-methoxyphenyl)oxazol-4-ylm-
ethyl]benzamide was obtained following the procedure of Example
3.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.10 (1H, d, J=7.8 Hz), 7.64-7.30
(6H, m), 7.15 (1H, d, J=8.4 Hz), 6.94 (1H, d, J=8.1 Hz), 6.61 (1H,
t, J=75 Hz), 4.70-4.61 (5H, m), 3.91 (3H, s), 1.39 (6H, d, J=6.0
Hz)
Example 324
Using the compound obtained in Example 17 and 3-bromopentane, white
powdery N-{2-[3-(1-ethylpropoxy)-4-methoxy
phenyl]oxazol-4-ylmethyl}-3-methylpicolinamide was obtained
following the procedure of Example 3.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.58 (1H, br s), 8.39 (1H, d,
J=4.5 Hz), 7.63-7.55 (4H, m), 7.32-7.28 (1H, m), 6.92 (1H, d, J=8.4
Hz), 4.59 (2H, d, J=6.0 Hz), 4.28-4.20 (1H, m), 3.90 (3H, s), 2.76
(3H, s), 1.82-1.68 (4H, m), 0.99 (6H, t, J=7.5 Hz)
Example 325
Using the compound obtained in Example 2 and 3-bromopentane, white
powdery
2-ethoxy-N-{2-[3-(1-ethylpropoxy)-4-methoxyphenyl]oxazol-4-ylmeth-
yl}benzamide was obtained following the procedure of Example 3.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.57 (1H, br s), 8.24 (1H, dd,
J=8.1, 1.8 Hz), 7.62-7.56 (3H, m), 7.45-7.39 (1H, m), 7.07 (1H, t,
J=8.1 Hz), 6.96-6.91 (2H, m), 4.63 (2H, dd, J=5.4, 0.9 Hz),
4.26-4.14 (3H, m), 3.90 (3H, s), 1.79-1.69 (4H, m), 1.49 (3H, t,
J=7.2 Hz), 1.00 (6H, t, J=7.2 Hz)
Reference Example 92
Using the compound obtained in Reference Example 44, colorless oily
dimethyl 2-[2-(3-benzyloxy-4-difluoromethoxy
phenyl)oxazol-4-ylmethyl]malonate was obtained following the
procedure of Reference Example 47.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.70 (1H, s), 7.59 (1H, d, J=7.8
Hz), 7.48-7.22 (6H, m), 6.62 (1H, t, J=74.7 Hz), 5.21 (2H, s), 3.90
(1H, t, J=7.5 Hz), 3.73 (6H, s), 3.20 (2H, t, J=7.5 Hz)
Reference Example 93
Using the compound obtained in Reference Example 92, pale yellow
oily methyl 3-[2-(3-benzyloxy-4-difluoromethoxy
phenyl)oxazol-4-yl]propionate was obtained following the procedure
of Reference Example 48.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.71 (1H, d, J=1.8 Hz), 7.48-7.31
(6H, m), 7.24 (1H, d, J=8.4 Hz), 6.62 (1H, t, J=74.7 Hz), 5.21 (2H,
s), 3.70 (3H, s), 2.93 (2H, t, J=7.2 Hz), 2.71 (2H, t, J=7.2
Hz)
Example 326
Using the compound obtained in Reference Example 93, colorless oily
methyl 2-[2-(3-benzyloxy-4-difluoromethoxy
phenyl)oxazol-4-ylmethyl]-3-(3-methylpyridin-2-yl)-3-oxo propionate
was obtained following the procedure of Example 100.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.50 (1H, dd, J=4.8, 1.2 Hz),
7.67-7.30 (10H, m), 7.21 (1H, d, J=8.4 Hz), 6.60 (1H, t, J=74.7
Hz), 5.18 (2H, s), 4.11 (1H, t, J=7.2 Hz), 3.65 (3H, s), 3.45-3.20
(2H, m), 2.60 (3H, s)
Example 327
The compound obtained in Example 326 was used and treated following
the procedure of Example 125, followed by treatment according to
the procedure of Example 2, yielding white powdery
3-[2-(4-difluoromethoxy-3-hydroxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-
-yl)propan-1-one.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.50 (1H, dd, J=4.5, 1.2 Hz),
7.67-7.45 (4H, m), 7.33-7.30 (1H, m), 7.16 (1H, d, J=8.1 Hz), 6.58
(1H, t, J=75 Hz), 5.76 (1H, s), 3.60 (2H, t, J=7.5 Hz), 3.01 (2H,
t, J=7.5 Hz), 2.57 (3H, s)
Example 328
A 0.15 quantity of the compound obtained in Example 327 and 0.18 ml
of 1,8-diazabicyclo[5,4,0]undec-7-ene were dissolved in 3 ml of
ethanol, 0.15 g of (bromomethyl)cyclopropane was then added to the
obtained solution, and the obtained mixture was heated and refluxed
overnight. After cooling, water was added to the obtained reaction
mixture, and ethyl acetate extraction was performed. The organic
layer was washed twice with water and concentrated under reduced
pressure, and the obtained residue was purified by silica gel
column chromatography (n-hexane:ethyl acetate=3:1). The obtained
crystals were recrystallized from aqueous 80% ethanol, thereby
yielding 42 mg of white powdery
3-[2-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)oxazol-4-yl]-1-(3-meth-
ylpyridin-2-yl)propan-1-one.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.51 (1H, dd, J=4.8, 1.2 Hz),
7.60-7.53 (3H, m), 7.50 (1H, s), 7.35-7.31 (1H, m), 7.21 (1H, d,
J=8.1 Hz), 6.68 (1H, t, J=75.3 Hz), 3.95 (2H, d, J=6.9 Hz), 3.60
(2H, t, J=7.5 Hz), 3.02 (2H, t, J=7.5 Hz), 2.58 (3H, s), 1.37-1.25
(1H, m), 0.69-0.63 (2H, m), 0.40-0.34 (2H, m)
Example 329
A 80 mg quantity of the compound obtained in Example 327 and 0.09
ml of 1,8-diazabicyclo[5,4,0]undec-7-ene were dissolved in 2 ml of
ethanol, 80 mg of 1-bromopropane was then added to the obtained
solution, and heated and refluxed overnight. After cooling, water
was added to the obtained reaction mixture, and ethyl acetate
extraction was performed. The organic layer was washed twice with
water, concentrated under reduced pressure, and the obtained
residue was purified by silica gel column chromatography
(n-hexane:ethyl acetate=3:1). The obtained crystals were
recrystallized from aqueous 80% ethanol, thereby yielding 25 mg of
white powdery
3-[2-(4-difluoromethoxy-3-propoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-
-yl)propan-1-one.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.51 (1H, dd, J=4.8, 1.2 Hz),
7.61-7.53 (3H, m), 7.50 (1H, s), 7.35-7.31 (1H, m), 7.20 (1H, d,
J=8.1 Hz), 6.61 (1H, t, J=75 Hz), 4.07 (2H, t, J=6.6 Hz), 3.60 (2H,
t, J=7.5 Hz), 3.02 (2H, t, J=7.5 Hz), 2.58 (3H, s), 1.87 (2H, td,
J=7.5, 6.6 Hz), 1.07 (3H, t, J=7.5 Hz)
Example 330
A 0.15 g quantity of the compound obtained in Example 327 and 0.18
ml of 1,8-diazabicyclo[5,4,0]undec-7-ene were dissolved in 3 ml of
ethanol, 0.15 g of allyl bromide was then added to the obtained
solution, and heating and refluxing were conducted for 2 hours.
After cooling, water was added to the obtained reaction mixture,
and ethyl acetate was performed. The organic layer was washed twice
with water, concentrated, and the obtained residue was purified by
silica gel column chromatography (n-hexane:ethyl acetate=3:1). The
obtained crystals were recrystallized from aqueous 80% ethanol,
thereby yielding 70 mg of white powdery
3-[2-(3-allyloxy-4-difluoromethoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin--
2-yl)propan-1-one.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.51 (1H, dd, J=4.5, 1.2 Hz),
7.62-7.56 (3H, m), 7.50 (1H, s), 7.50-7.31 (1H, m), 7.22 (1H, d,
J=8.4 Hz), 6.62 (1H, t, J=75 Hz), 6.12-6.02 (1H, m), 5.46 (1H, dd,
J=17.4, 1.5 Hz), 5.33 (1H, dd, J=10.8, 1.5 Hz), 4.68 (2H, d, J=8.1
Hz), 3.61 (2H, t, J=7.2 Hz), 3.02 (2H, t, J=7.2 Hz), 2.58 (3H,
s)
Example 331
An 80 mg quantity of the compound obtained in Example 327 and 0.09
ml of 1,8-diazabicyclo[5,4,0]undec-7-ene were dissolved in 2 ml of
ethanol, and 80 mg of 4-bromo-1-butene was then added to the
obtained solution, and heating and refluxing were conducted
overnight. After cooling, water was added to the obtained reaction
mixture, and ethyl acetate extraction was performed. The organic
layer was washed twice with water, concentrated under reduced
pressure, and the obtained residue was purified by silica gel
column chromatography (n-hexane:ethyl acetate=3:1). The obtained
crystals were recrystallized from aqueous 80% ethanol, thereby
yielding 22 mg of white powdery
3-[2-(3-but-3-enyloxy-4-difluoromethoxyphenyl)-oxazol-4-yl]-1-(3-methylpy-
ridin-2-yl)propan-1-one
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.51 (1H, dd, J=4.8, 1.2 Hz),
7.61-7.54 (3H, m), 7.50 (1H, s), 7.35-7.31 (1H, m), 7.20 (1H, d,
J=8.4 Hz), 6.62 (1H, t, J=75 Hz), 5.98-5.83 (1H, m), 5.24-5.12 (2H,
m), 4.16 (2H, t, J=6.6 Hz), 3.61 (2H, t, J=7.2 Hz), 3.03 (2H, t,
J=7.2 Hz), 2.64-2.58 (5H, m)
Example 332
A 0.15 g quantity of the compound obtained in Example 327 and 0.18
ml of DBU were dissolved in 3 ml of ethanol, 0.15 g of
2-bromopropane was then added to the obtained solution, and heating
and refluxing were conducted overnight. After cooling, water was
added to the reaction mixture, and ethyl acetate extraction was
performed. The organic layer was washed twice with water,
concentrated under reduced pressure, and the obtained residue was
purified by silica gel column chromatography (n-hexane:ethyl
acetate=3:1). The obtained crystals were recrystallized from
aqueous 80% ethanol, thereby yielding 70 mg of white powdery
3-[2-(4-difluoromethoxy-3-isopropoxyphenyl)oxazol-4-yl]-1-(3-methylpyridi-
n-2-yl)propan-1-one
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.51 (1H, dd, J=4.8, 0.9 Hz),
7.63-7.53 (3H, m), 7.50 (1H, s), 7.35-7.31 (1H, m), 7.20 (1H, d,
J=8.1 Hz), 6.61 (1H, t, J=75 Hz), 4.73-4.65 (1H, m), 3.61 (2H, t,
J=7.2 Hz), 3.02 (2H, t, J=7.2 Hz), 2.58 (3H, s), 1.39 (6H, d, J=6.0
Hz)
Example 333
Using the compound obtained in Example 327 and ethyl iodide, white
powdery
3-[2-(4-difluoromethoxy-3-ethoxyphenyl)oxazol-4-yl]-1-(3-methylpy-
ridin-2-yl)propan-1-one was obtained following the procedure of
Example 330.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.50 (1H, dd, J=4.5, 1.2 Hz),
7.61-7.49 (4H, m), 7.35-7.30 (1H, m), 7.20 (1H, d, J=8.4 Hz), 6.62
(1H, t, J=75 Hz), 4.18 (2H, q, J=6.9 Hz), 3.61 (2H, t, J=7.2 Hz),
3.02 (2H, t, J=7.2 Hz), 2.58 (3H, s), 1.47 (3H, t, J=6.9 Hz)
Example 334
A 60 mg quantity of the compound obtained in Example 229 and 0.2 ml
of DBU were dissolved in 4 ml of ethanol, 0.2 ml of ethyl iodide
was then added to the obtained solution, and heating and refluxing
were conducted for 2 hours. After cooling, water was added to the
reaction mixture, and ethyl acetate extraction was performed. The
organic layer was washed twice with water, concentrated under
reduced pressure, and the obtained residue was purified by silica
gel column chromatography (n-hexane:ethyl acetate=3:1). The
obtained crystals were recrystallized from ethanol, thereby
yielding 36 mg of white powdery
3-[2-(4-difluoromethoxy-3-ethoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)pro-
pan-1-one.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.71 (1H, dd, J=7.5, 1.8 Hz),
7.60-7.34 (4H, m), 7.01-6.91 (2H, m), 7.20 (1H, d, J=8.1 Hz), 6.62
(1H, t, J=75 Hz), 4.22-4.07 (4H, m), 3.43 (2H, t, J=7.2 Hz), 3.00
(2H, t, J=7.2 Hz), 1.50-1.40 (6H, m)
Example 335
A 0.15 g quantity of the compound obtained in Example 229 and 0.17
ml of DBU were dissolved in 4 ml of ethanol, 0.14 g of ally bromide
was then added to the obtained solution, and heating and refluxing
were conducted for 2 hours. After cooling, water was added to the
obtained reaction mixture, and ethyl acetate extraction was
performed. The organic layer was washed twice with water,
concentrated under reduced pressure, and the obtained residue was
purified by silica gel column chromatography (n-hexane:ethyl
acetate=3:1). The obtained crystals were recrystallized from
aqueous 80% ethanol, thereby yielding 90 mg of white powdery
3-[2-(3-allyloxy-4-difluoromethoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)p-
ropan-1-one.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.71 (1H, dd, J=7.5, 1.8 Hz),
7.62-7.56 (2H, m), 7.46-7.40 (2H, m), 7.22 (1H, d, J=8.1 Hz),
7.01-6.92 (2H, m), 6.62 (1H, t, J=75 Hz), 6.15-6.00 (1H, m), 5.45
(1H, dd, J=17.1, 1.5 Hz), 5.32 (1H, dd, J=10.5, 1.5 Hz), 4.67 (2H,
d, J=8.1 Hz), 4.14 (2H, q, J=6.9 Hz), 3.42 (2H, t, J=7.5 Hz), 3.00
(2H, t, J=7.5 Hz), 1.48 (3H, t, J=6.9 Hz)
Example 336
A 0.12 g quantity of the compound obtained in Example 229 and 0.14
ml of DBU were dissolved in 3 ml of ethanol, 0.12 g of
(bromomethyl)cyclopropane was then added to the obtained solution,
and heating and refluxing were conducted overnight. After cooling,
water was added to the obtained reaction mixture, and ethyl acetate
extraction was performed. The organic layer was washed twice with
water, concentrated under reduced pressure, and the obtained
residue was purified by silica gel column chromatography
(n-hexane:ethyl acetate=3:1). The obtained crystals were
recrystallized from ethanol, thereby yielding 80 mg of white
powdery 3-[2-(3-cyclopropylmethoxy-4-difluoromethoxy
phenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-one.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.71 (1H, dd, J=7.8, 1.8 Hz),
7.59-7.54 (2H, m), 7.46-7.40 (2H, m), 7.21 (1H, d, J=8.1 Hz),
7.01-6.95 (2H, m), 6.68 (1H, t, J=75 Hz), 4.14 (2H, q, J=6.9 Hz),
3.95 (2H, d, J=6.9 Hz), 3.42 (2H, t, J=7.2 Hz), 3.00 (2H, t, J=7.2
Hz), 1.47 (3H, t, J=6.9 Hz), 1.34-1.28 (1H, m), 0.69-0.63 (2H, m),
0.40-0.34 (2H, m)
Example 337
A 0.12 g quantity of the compound obtained in Example 229 and 0.14
ml of DBU were dissolved in 3 ml of ethanol, 0.12 g of
4-bromo-1-butene was then added to the obtained solution, and
heating and refluxing were conducted overnight. After cooling,
water was added to the obtained reaction mixture, and ethyl acetate
extract was performed. The organic layer was washed twice with
water, concentrated under reduced pressure, and the obtained
residue was purified by silica gel column chromatography
(n-hexane:ethyl acetate=3:1). The obtained crystals were
recrystallized from ethanol, thereby yielding 80 mg of white
powdery
3-[2-(3-but-3-enyloxy-4-difluoromethoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphe-
nyl)propan-1-one.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.70 (1H, dd, J=7.8, 1.8 Hz),
7.61-7.54 (2H, m), 7.45-7.40 (2H, m), 7.20 (1H, d, J=8.1 Hz),
7.00-6.92 (2H, m), 6.62 (1H, t, J=75 Hz), 5.97-5.83 (1H, m),
5.23-5.12 (2H, m), 4.18-4.10 (4H, m), 3.42 (2H, t, J=7.2 Hz), 3.00
(2H, t, J=7.2 Hz), 2.63-2.56 (4H, m), 1.47 (3H, t, J=6.9 Hz)
Example 338
Using the compound obtained in Example 97 and ethyl iodide, white
powdery
N-[2-(4-difluoromethoxy-3-ethoxyphenyl)-oxazol-4-ylmethyl]-3-methylpicoli-
namide was obtained following the procedure of Example 3.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.60 (1H, br s), 8.39 (1H, d,
J=3.6 Hz), 7.67-7.57 (4H, m), 7.33-7.20 (2H, m), 6.63 (1H, t, J=75
Hz), 4.60 (2H, d, J=5.7 Hz), 4.20 (2H, q, J=6.9 Hz), 2.76 (3H, s),
1.48 (3H, t, J=6.9 Hz)
Example 339
Using the compound obtained in Example 97 and allyl bromide, white
solid N-[2-(3-allyloxy-4-difluoromethoxy
phenyl)oxazol-4-ylmethyl]-3-methylpicolinamide was obtained
following the procedure of Example 3.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.60 (1H, br s), 8.40-8.39 (1H,
m), 7.67 (1H, s), 7.65-7.58 (3H, m), 7.33-7.22 (3H, m), 6.63 (1H,
t, J=75 Hz), 6.13-6.03 (1H, m), 5.50-5.32 (2H, m), 4.70-4.68 (2H,
m), 4.60 (2H, d, J=8.7 Hz), 2.76 (3H, s)
Example 340
Using the compound obtained in Example 97 and 1-bromopropane, white
powdery
N-[2-(4-difluoromethoxy-3-propoxyphenyl)oxazol-4-ylmethyl]-3-meth-
ylpicolinamide was obtained following the procedure of Example
3.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.58 (1H, br s), 8.39 (1H, d,
J=7.8, Hz), 7.67-7.57 (4H, m), 7.33-7.20 (2H, m), 6.62 (1H, t, J=75
Hz), 4.60 (2H, d, J=6.0 Hz), 4.08 (2H, t, J=6.6 Hz), 2.76 (3H, s),
1.94-1.82 (2H, m), 1.07 (3H, t, J=7.5 Hz)
Example 341
Using the compound obtained in Example 97 and 2-bromopropane, white
solid
N-[2-(4-difluoromethoxy-3-isopropoxyphenyl)oxazol-4-ylmethyl]-3-methylpic-
olinamide was obtained following the procedure of Example 3.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.58 (1H, br s), 8.39-8.38 (1H,
m), 7.67-7.57 (4H, m), 7.33-7.19 (2H, m), 6.62 (1H, t, J=75 Hz),
4.74-4.67 (1H, m), 4.59 (2H, d, J=6.0 Hz), 2.76 (3H, s), 1.39 (6H,
d, J=6.0 Hz)
Example 342
Using the compound obtained in Example 97 and 3-bromopentane,
colorless oily
N-{2-[4-difluoromethoxy-3-(1-ethylpropoxy)phenyl]oxazol-4-ylmethyl}--
3-methylpicolinamide was obtained following the procedure of
Example 3.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.58 (1H, br s), 8.40-8.38 (1H,
m), 7.67 (1H, s), 7.63-7.55 (3H, m), 7.33-7.20 (3H, m), 6.61 (1H,
t, J=75 Hz), 4.59 (2H, d, J=6.0 Hz), 4.33 (1H, qt, J=6.0 Hz), 2.76
(3H, s), 1.79-1.70 (4H, m), 0.98 (6H, t, J=7.2 Hz)
Example 343
Using the compound obtained in Example 97 and 4-bromo-1-butene,
colorless oily N-[2-(3-but-3-enyloxy-4-difluoromethoxy
phenyl)oxazol-4-ylmethyl]-3-methylpicolinamide was obtained
following the procedure of Example 3.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.58 (1H, br s), 8.40-8.38 (1H,
m), 7.67 (1H, s), 7.64-7.58 (3H, m), 7.33-7.20 (2H, m), 6.63 (1H,
t, J=75 Hz), 5.95-5.84 (1H, m), 5.23-5.13 (2H, m), 4.61-4.59 (2H,
m), 4.18 (2H, t, J=6.6 Hz), 2.76 (3H, s), 2.64-2.58 (2H, m)
Example 344
Using the compound obtained in Example 97 and isobutyl bromide,
colorless oily N-[2-(4-difluoromethoxy-3-isobutoxy
phenyl)oxazol-4-ylmethyl]-3-methylpicolinamide was obtained
following the procedure of Example 3.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.60 (1H, br s), 8.39 (1H, br s),
7.68 (1H, s), 7.62-7.57 (3H, m), 7.33-7.20 (2H, m), 6.61 (1H, t,
J=75 Hz), 4.60 (2H, d, J=6.0 Hz), 3.88 (2H, d, J=6.3 Hz), 2.76 (3H,
s), 2.19-2.04 (1H, m), 1.06 (6H, d, J=6.3 Hz)
Example 345
Using the compound obtained in Example 97 and
(bromomethyl)cyclobutane, colorless oily N-[2-(3-cyclobutyl
methoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-3-methyl
picolinamide was obtained following the procedure of Example 3.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.60 (1H, br s), 8.40 (1H, br s),
7.68 (1H, s), 7.64-7.59 (3H, m), 7.33-7.20 (2H, m), 6.61 (1H, t,
J=75 Hz), 4.60 (2H, d, J=6.0 Hz), 4.08 (2H, d, J=6.6 Hz), 2.89-2.76
(4H, m), 2.25-2.12 (2H, m), 2.04-1.92 (4H, m)
Example 346
Using the compound obtained in Reference Example 46 and
2-ethoxybenzoic acid, white powdery N-[2-(3-benzyloxy-4-difluoro
methoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide was obtained
following the procedure of Example 96.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.56 (1H, br s), 8.24 (1H, dd,
J=7.8, 1.8 Hz), 7.73 (1H, d, J=1.8 Hz), 7.68-7.61 (2H, m),
7.48-7.24 (7H, m), 7.07 (1H, t, J=8.1 Hz), 6.95 (1H, d, J=8.4 Hz),
6.63 (1H, t, J=75 Hz), 5.21 (2H, s), 4.63 (2H, d, J=5.4 Hz), 4.18
(2H, q, J=6.9 Hz), 1.48 (3H, t, J=6.9 Hz)
Example 347
Using the compound obtained in Example 346, white powdery
N-[2-(4-difluoromethoxy-3-hydroxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzam-
ide was obtained following the procedure of Example 97.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.60 (1H, br s), 8.23 (1H, dd,
J=7.8, 1.8 Hz), 7.71-7.60 (2H, m), 7.57 (1H, dd, J=8.4, 1.8 Hz),
7.46-7.39 (1H, m), 7.19 (1H, d, J=8.4 Hz), 7.07 (1H, t, J=8.1 Hz),
6.95 (1H, d, J=8.4 Hz), 6.61 (1H, t, J=73.2 Hz), 6.02 (1H, br s),
4.64 (2H, dd, J=5.4, 0.9 Hz), 4.19 (2H, q, J=6.9 Hz), 1.49 (3H, t,
J=6.9 Hz)
Example 348
A 80 mg quantity of the compound obtained in Example 347 and 0.1 ml
of DBU were dissolved in 2 ml of ethanol, 80 mg of isobutyl bromide
was then added to the obtained solution, and heating and refluxing
were conducted overnight. After cooling, water was added to the
obtained reaction mixture, and ethyl acetate extraction was
performed. The organic layer was washed twice with water,
concentrated under reduced pressure, and the obtained residue was
purified by silica gel column chromatography (n-hexane:ethyl
acetate=3:1). The obtained crystals were recrystallized from
aqueous 80% ethanol, thereby yielding 30 mg of white powdery
N-[2-(4-difluoromethoxy-3-isobutoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenz-
amide.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.54 (1H, br s), 8.24 (1H, dd,
J=7.8, 1.8 Hz), 7.67 (1H, s), 7.66-7.57 (2H, m), 7.45-7.39 (1H, m),
7.23 (1H, d, J=8.1 Hz), 7.07 (1H, t, J=8.1 Hz), 6.95 (1H, d, J=7.5
Hz), 6.62 (1H, t, J=75 Hz), 4.64 (2H, d, J=5.1 Hz), 4.19 (2H, q,
J=6.9 Hz), 3.87 (2H, d, J=6.6 Hz), 2.17 (1H, qt, J=6.6 Hz), 1.49
(3H, t, J=6.9 Hz), 1.07 (6H, d, J=6.9 Hz)
Example 349
Using the compound obtained in Example 347 and ethyl iodide, white
powdery
N-[2-(4-difluoromethoxy-3-ethoxyphenyl)oxazol-4-ylmethyl]-2-ethox-
ybenzamide was obtained following the procedure of Example 348.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.56 (1H, br s), 8.24 (1H, dd,
J=7.8, 1.8 Hz), 7.67-7.58 (3H, m), 7.46-7.40 (1H, m), 7.24-7.21
(1H, m), 7.08 (1H, t, J=7.8 Hz), 6.95 (1H, d, J=7.8 Hz), 6.64 (1H,
t, J=75 Hz) 4.63 (1H, d, J=5.1 Hz), 4.23-4.15 (4H, m), 1.52-1.46
(6H, m)
Example 350
Using the compound obtained in Example 347 and 1-bromopropane,
white powdery N-[2-(4-difluoromethoxy-3-propoxy
phenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide was obtained following
the procedure of Example 348.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.56 (1H, br s), 8.24 (1H, dd,
J=7.5, 1.8 Hz), 7.67 (1H, s), 7.64-7.57 (2H, m), 7.46-7.40 (1H, m),
7.23 (1H, d, J=7.8 Hz), 7.07 (1H, t, J=7.5 Hz), 6.95 (1H, d, J=8.4
Hz), 6.63 (1H, t, J=75 Hz), 4.64 (2H, d, J=5.4 Hz), 4.19 (2H, q,
J=7.2 Hz), 4.07 (2H, t, J=6.6 Hz), 1.90 (2H, qt, J=7.2, 6.6 Hz),
1.49 (3H, t, J=6.9 Hz), 1.08 (3H, t, J=7.2 Hz)
Example 351
Using the compound obtained in Example 347 and allyl bromide, white
powdery N-[2-(3-allyloxy-4-difluoromethoxy
phenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide was obtained following
the procedure of Example 348.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.55 (1H, br s), 8.24 (1H, dd,
J=7.8, 1.8 Hz), 7.68 (1H, s), 7.65-7.60 (2H, m), 7.46-7.40 (1H, m),
7.25-7.23 (1H, m), 7.08 (1H, t, J=7.8 Hz), 6.96 (1H, d, J=8.4 Hz),
6.64 (1H, t, J=74.7 Hz), 6.10-6.03 (1H, m), 5.47 (1H, dd, J=17.4,
1.5 Hz), 5.34 (1H, dd, J=10.5, 1.5 Hz), 4.69 (2H, dt, J=5.1, 1.5
Hz), 4.63 (2H, dd, J=5.4, 1.2 Hz), 4.19 (2H, q, J=6.9 Hz), 1.49
(3H, t, J=6.9 Hz)
Example 352
Using the compound obtained in Example 347 and 2-bromopropane,
white powdery
N-[2-(4-difluoromethoxy-3-isopropoxyphenyl)oxazol-4-ylmethyl]-2-e-
thoxybenzamide was obtained following the procedure of Example
348.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.57 (1H, br s), 8.24 (1H, dd,
J=7.5, 1.8 Hz), 7.67 (1H, s), 7.65-7.57 (2H, m), 7.46-7.40 (1H, m),
7.26-7.21 (1H, m), 7.08 (1H, t, J=7.5 Hz), 6.95 (1H, d, J=8.4 Hz),
6.63 (1H, t, J=75 Hz), 4.74-4.62 (3H, m), 4.19 (2H, q, J=6.9 Hz),
1.49 (3H, t, J=6.9 Hz), 1.40 (6H, d, J=6.3 Hz)
Example 353
Using the compound obtained in Example 347 and
(bromomethyl)cyclopropane, white powdery N-[2-(3-cyclopropyl
methoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-ethoxy
benzamide was obtained following the procedure of Example 348.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.55 (1H, br s), 8.24 (1H, dd,
J=8.1, 1.8 Hz), 7.67 (1H, s), 7.61-7.58 (2H, m), 7.46-7.39 (1H, m),
7.26-7.21 (1H, m), 7.07 (1H, t, J=7.5 Hz), 6.95 (1H, d, J=8.4 Hz),
6.70 (1H, t, J=75 Hz) 4.63 (2H, dd, J=5.4, 0.9 Hz), 4.19 (2H, q,
J=6.9 Hz), 1.49 (3H, t, J=6.9 Hz), 1.35-1.30 (1H, m), 0.71-0.64
(2H, m), 0.41-0.35 (2H, m)
Example 354
Using the compound obtained in Example 347 and 4-bromo-1-butene,
white powdery N-[2-(3-but-3-enyloxy-4-difluoromethoxy
phenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide was obtained following
the procedure of Example 348.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.56 (1H, br s), 8.24 (1H, dd,
J=7.5, 1.8 Hz), 7.67 (1H, s), 7.64-7.58 (2H, m), 7.46-7.40 (1H, m),
7.26-7.21 (1H, m), 7.08 (1H, t, J=7.5 Hz), 6.95 (1H, d, J=8.4 Hz),
6.64 (1H, t, J=75 Hz), 5.92-5.86 (1H, m), 5.24-5.13 (2H, m), 4.64
(2H, d, J=5.1 Hz), 4.22-4.14 (4H, m), 2.65-2.58 (2H, m), 1.49 (3H,
t, J=6.9 Hz)
Example 355
Using the compound obtained in Example 347 and 3-bromopentane,
white powdery
N-{2-[4-difluoromethoxy-3-(1-ethylpropoxy)phenyl]oxazol-4-ylmethy-
l}-2-ethoxybenzamide was obtained following the procedure of
Example 348.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.57 (1H, br s), 8.24 (1H, dd,
J=7.8, 1.8 Hz), 7.67 (1H, s), 7.63-7.58 (2H, m), 7.46-7.40 (1H, m),
7.23 (1H, d, J=8.4 Hz), 7.07 (1H, t, J=8.1 Hz), 6.95 (1H, d, J=8.1
Hz), 6.63 (1H, t, J=75 Hz), 4.64 (2H, d, J=5.1 Hz), 4.33 (1H, qt,
J=6.0, 5.1 Hz), 4.19 (2H, q, J=6.9 Hz), 1.79-1.70 (4H, m), 1.49
(3H, t, J=6.9 Hz), 0.99 (6H, t, J=7.5 Hz)
Reference Example 94
Using the compound obtained in Reference Example 59 and
chlorodifluoromethane, white powdery ethyl
4-benzyloxy-3-difluoromethoxybenzoate was obtained following the
procedure of Example 4.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.90-7.80 (2H, m), 7.45-7.30 (5H,
m), 7.03 (1H, d, J=8.4 Hz), 6.59 (1H, t, J=74.4 Hz), 5.23 (2H, s),
4.35 (2H, q, J=7.2 Hz), 1.38 (3H, t, J=7.2 Hz)
Reference Example 95
Using the compound obtained in Reference Example 94, white powdery
2-(4-benzyloxy-3-difluoromethoxyphenyl)-4-chloromethyloxazole was
obtained following the procedures of Reference Examples 3 to 5.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.90-7.80 (2H, m), 7.65 (1H, s),
7.45-7.30 (5H, m), 7.06 (1H, d, J=7.2 Hz), 6.60 (1H, t, J=74.7 Hz),
5.20 (2H, s), 4.56 (2H, s)
Example 356
Using the compound obtained in Reference Example 95, white powdery
3-{2-(3-difluoromethoxy-4-hydroxyphenyl)oxazol-4-yl}-1-(3-methylpyridin-2-
-yl)propan-1-one was obtained following the procedures of Reference
Examples 92 and 93 and Examples 326 and 327.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.49 (1H, d, J=4.5 Hz), 7.76-7.72
(2H, m), 7.59 (1H, d, J=8.4 Hz), 7.57 (1H, s), 7.37-7.30 (1H, m),
7.02 (1H, d, J=8.4 Hz), 6.59 (1H, t, J=75 Hz), 3.59 (2H, t, J=7.5
Hz), 3.01 (2H, t, J=7.5 Hz), 2.57 (3H, s)
Example 357
Using the compound obtained in Example 356 and 2-bromopropane,
white powdery 3-[2-(3-difluoromethoxy-4-isopropoxy
phenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one was
obtained following the procedure of Example 3.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.50 (1H, d, J=4.5 Hz), 7.83-7.78
(2H, m), 7.58 (1H, d, J=8.4 Hz), 7.47 (1H, s), 7.34-7.30 (1H, m),
7.01 (1H, d, J=8.4 Hz), 6.58 (1H, t, J=75 Hz), 4.67-4.57 (1H, m),
3.59 (2H, t, J=7.5 Hz), 3.01 (2H, t, J=7.5 Hz), 2.57 (3H, s), 1.39
(6H, d, J=6.0 Hz)
Example 358
Using the compound obtained in Example 356 and allyl bromide, white
powdery 3-[2-(4-allyloxy-3-difluoromethoxy
phenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one was
obtained following the procedure of Example 3.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.50 (1H, dd, J=4.8, 1.2 Hz),
7.84-7.80 (2H, m), 7.60-7.56 (1H, m), 7.47 (1H, d, J=1.2 Hz),
7.34-7.30 (1H, m), 7.01 (1H, d, J=8.4 Hz), 6.60 (1H, t, J=74.7 Hz),
6.10-6.00 (1H, m), 5.44 (1H, dd, J=17.4, 1.5 Hz), 5.33 (1H, dd,
J=10.5, 1.5 Hz), 4.65 (2H, dt, J=5.1, 1.5 Hz), 3.60 (2H, t, J=7.5
Hz), 3.01 (2H, t, J=7.5 Hz), 2.58 (3H, s)
Example 359
Using the compound obtained in Example 356 and 4-bromo-1-butene,
white powdery 3-[2-(4-but-3-enyloxy-3-difluoromethoxy
phenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one was
obtained following the procedure of Example 3.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.50 (1H, dd, J=4.8, 1.2 Hz),
7.84-7.78 (2H, m), 7.58 (1H, d, J=7.5 Hz), 7.46 (1H, s), 7.34-7.30
(1H, m), 7.00 (1H, d, J=8.4 Hz), 6.59 (1H, t, J=75 Hz), 5.94-5.85
(1H, m), 5.23-5.12 (2H, m), 4.12 (2H, t, J=6.6 Hz), 3.60 (2H, t,
J=7.2 Hz), 3.00 (2H, t, J=7.2 Hz), 2.63-2.56 (5H, m)
Example 360
Using the compound obtained in Example 356 and
(bromomethyl)cyclopropane, white powdery 3-[2-(4-cyclopropyl
methoxy-3-difluoromethoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)prop-
an-1-one was obtained following the procedure of Example 3.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.50 (1H, dd, J=4.8, 1.2 Hz),
7.83-7.79 (2H, m), 7.57 (1H, d, J=7.5 Hz), 7.46 (1H, s), 7.34-7.30
(1H, m), 6.98 (1H, d, J=8.1 Hz), 6.65 (1H, t, J=75 Hz), 3.92 (2H,
d, J=7.2 Hz), 3.59 (2H, t, J=7.2 Hz), 3.00 (2H, t, J=7.2 Hz), 2.57
(3H, s), 1.33-1.27 (1H, m), 0.69-0.63 (2H, m), 0.40-0.34 (2H,
m)
Example 361
Using the compound obtained in Example 356 and 1-bromopropane,
white powdery 3-[2-(3-difluoromethoxy-4-propoxy
phenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one was
obtained following the procedure of Example 3.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.50 (1H, dd, J=4.8, 1.2 Hz),
7.84-7.78 (2H, m), 7.58 (1H, d, J=8.1 Hz), 7.47 (1H, s), 7.43-7.30
(1H, m), 7.00 (1H, d, J=8.4 Hz), 6.59 (1H, t, J=75 Hz), 4.03 (2H,
t, J=6.6 Hz), 3.59 (2H, t, J=7.5 Hz), 3.01 (2H, t, J=7.5 Hz), 2.58
(3H, s), 1.87 (2H, qt, J=7.2 Hz), 1.06 (3H, t, J=7.2 Hz)
Example 362
Using the compound obtained in Example 356 and ethyl iodide, white
powdery
3-[2-(3-difluoromethoxy-4-ethoxyphenyl)oxazol-4-yl]-1-(3-methylpy-
ridin-2-yl)propan-1-one was obtained following the procedure of
Example 3.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.50 (1H, d, J=4.5 Hz), 7.84-7.78
(2H, m), 7.59 (1H, d, J=8.4 Hz), 7.47 (1H, s), 7.34-7.30 (1H, m),
6.99 (1H, d, J=8.4 Hz), 6.60 (1H, t, J=75 Hz), 4.15 (2H, q, J=6.9
Hz), 3.59 (2H, t, J=7.2 Hz), 3.01 (2H, t, J=7.2 Hz), 2.57 (3H, s),
1.47 (3H, t, J=6.9 Hz)
Example 363
The compound obtained in Reference Example 95 was used and treated
following the procedure of Example 228, followed by treatment
according to the procedure of Example 229, yielding white powdery
3-[2-(3-difluoromethoxy-4-hydroxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)pr-
opan-1-one.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.80-7.75 (2H, m), 7.71 (1H, dd,
J=7.8, 1.8 Hz), 7.46-7.40 (2H, m), 7.22-6.69 (3H, m), 6.59 (1H, t,
J=75 Hz), 5.91 (1H, br s), 4.14 (2H, q, J=7.2 Hz), 3.42 (2H, t,
J=7.5 Hz), 2.99 (2H, t, J=7.5 Hz), 1.48 (3H, t, J=7.2 Hz)
Example 364
Using the compound obtained in Example 363 and 4-bromo-1-butene,
white powdery 3-[2-(4-but-3-enyloxy-3-difluoromethoxy
phenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-one was obtained
following the procedure of Example 3.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.84-7.79 (2H, m), 7.71 (1H, dd,
J=7.8, 1.8 Hz), 7.46-7.39 (2H, m), 7.01-6.92 (3H, m), 6.59 (1H, t,
J=75 Hz), 5.91-5.85 (1H, m), 5.23-5.12 (2H, m), 4.18-4.09 (4H, m),
3.42 (2H, t, J=6.9 Hz), 2.99 (2H, t, J=6.9 Hz), 2.60 (2H, m), 1.48
(3H, t, J=6.9 Hz)
Example 365
Using the compound obtained in Example 363 and allyl bromide, white
powdery 3-[2-(4-allyloxy-3-difluoromethoxy
phenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-one was obtained
following the procedure of Example 3.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.83-7.79 (2H, m), 7.70 (1H, dd,
J=7.8, 1.8 Hz), 7.46-7.39 (2H, m), 7.02-6.92 (3H, m), 6.60 (1H, t,
J=74.7 Hz), 6.06-6.00 (1H, m), 5.47-5.30 (2H, m), 4.66-4.63 (2H,
m), 4.14 (2H, q, J=6.9 Hz), 3.42 (2H, t, J=6.9 Hz), 2.99 (2H, t,
J=6.9 Hz), 1.48 (3H, t, J=6.9 Hz)
Example 366
Using the compound obtained in Example 363 and ethyl iodide, white
powdery
3-[2-(3-difluoromethoxy-4-ethoxyphenyl)oxazol-4-yl]-1-(2-ethoxyph-
enyl)propan-1-one was obtained following the procedure of Example
3.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.84-7.80 (2H, m), 7.71 (1H, dd,
J=7.8, 1.8 Hz), 7.45-7.39 (2H, m), 7.00-6.91 (3H, m), 6.60 (1H, t,
J=75 Hz) 4.18-4.10 (4H, m), 3.42 (2H, t, J=7.5 Hz), 2.99 (2H, t,
J=7.5 Hz), 1.50-1.44 (6H, m)
Reference Example 96
The compound obtained in Reference Example 95 was used and treated
following the procedure of Reference Example 45, followed by
treatment according to the procedure of Reference Example 46,
yielding pale yellow oily
[2-(4-benzyloxy-3-difluoromethoxyphenyl)oxazol-4-yl]methylamine was
obtained.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.89-7.82 (2H, m), 7.61 (1H, s),
7.56-7.31 (5H, m), 7.07 (1H, d, J=8.1 Hz), 6.62 (1H, t, J=75 Hz),
5.19 (2H, s), 3.83 (2H, s)
Example 367
The compound obtained in Reference Example 96 was used and treated
following the procedure of Example 96, followed by treatment
according to the procedure of Example 97, yielding white powdery
N-[2-(3-difluoromethoxy-4-hydroxyphenyl)oxazol-4-ylmethyl]-3-methylpicoli-
namide.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.59 (1H, br s), 8.39 (1H, d,
J=4.5 Hz), 7.79-7.76 (2H, m), 7.63-7.58 (2H, m), 7.37-7.28 (1H, m),
7.07 (1H, d, J=8.1 Hz), 6.61 (1H, t, J=75 Hz), 6.16 (1H, s), 4.58
(2H, d, J=5.4 Hz), 2.76 (3H, s)
Example 368
Using the compound obtained in Example 367 and allyl bromide, white
powdery N-[2-(4-allyloxy-3-difluoromethoxy
phenyl)oxazol-4-ylmethyl]-3-methylpicolinamide was obtained
following the procedure of Example 98.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.60 (1H, br s), 8.39 (1H, d,
J=4.5 Hz), 7.87-7.83 (2H, m), 7.65 (1H, s), 7.60-7.57 (1H, m),
7.33-7.29 (1H, m), 7.10 (1H, d, J=8.4 Hz), 6.61 (1H, t, J=75 Hz),
6.10-5.99 (1H, m), 5.55 (1H, dd, J=17.1, 1.5 Hz), 5.34 (1H, dd,
J=10.5, 1.5 Hz), 4.65 (2H, d, J=5.4 Hz), 4.58 (2H, d, J=5.4 Hz),
2.76 (3H, s)
Example 369
Using the compound obtained in Example 367 and
(bromomethyl)cyclobutane, white powdery N-[2-(4-cyclobutyl
methoxy-3-difluoromethoxyphenyl)oxazol-4-ylmethyl]-3-methyl
picolinamide was obtained following the procedure of Example
98.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.58 (1H, br s), 8.39 (1H, d,
J=4.5 Hz), 7.87-7.82 (2H, m), 7.64 (1H, s), 7.59 (1H, d, J=8.4 Hz),
7.33-7.29 (2H, m), 7.01 (1H, d, J=8.4 Hz), 6.59 (1H, t, J=75 Hz),
4.59 (1H, d, J=5.4 Hz), 4.03 (2H, d, J=6.9 Hz), 2.90-2.82 (1H, m),
2.76 (3H, s), 2.22-2.13 (2H, m), 2.00-1.84 (4H, m)
Example 370
Using the compound obtained in Example 367 and isobutyl bromide,
white powdery N-[2-(3-difluoromethoxy-4-isobutoxy
phenyl)oxazol-4-ylmethyl]-3-methylpicolinamide was obtained
following the procedure of Example 98.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.58 (1H, br s), 8.39 (1H, d,
J=4.5 Hz), 7.87-7.83 (2H, m), 7.64 (1H, s), 7.60-7.57 (1H, m),
7.33-7.28 (1H, m), 7.00 (1H, d, J=8.4 Hz), 6.59 (1H, t, J=75 Hz),
4.59 (1H, d, J=5.4 Hz), 3.81 (2H, d, J=6.9 Hz), 2.76 (3H, s),
2.22-2.09 (1H, m), 1.06 (6H, d, J=6.6 Hz)
Example 371
Using the compound obtained in Example 367 and 4-bromo-1-butene,
white powdery N-[2-(4-but-3-enyloxy-3-difluoromethoxy
phenyl)oxazol-4-ylmethyl]-3-methylpicolinamide was obtained
following the procedure of Example 98.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.59 (1H, br s), 8.39 (1H, d,
J=4.5 Hz), 7.88-7.83 (2H, m), 7.65 (1H, s), 7.60-7.57 (1H, m),
7.33-7.29 (1H, m), 7.01 (1H, d, J=8.4 Hz), 6.61 (1H, t, J=75 Hz),
5.94-5.83 (1H, m), 5.24-5.12 (2H, m), 4.59 (1H, d, J=5.4 Hz), 4.13
(2H, t, J=6.6 Hz), 2.76 (3H, s), 2.63-2.57 (2H, m)
Example 372
Using the compound obtained in Example 367 and
(bromomethyl)cyclopropane, white powdery N-[2-(4-cyclopropyl
methoxy-3-difluoromethoxyphenyl)oxazol-4-ylmethyl]-3-methyl
picolinamide was obtained following the procedure of Example
98.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.58 (1H, br s), 8.39 (1H, d,
J=4.5 Hz), 7.86-7.83 (2H, m), 7.65 (1H, s), 7.59 (1H, d, J=8.4 Hz),
7.33-7.28 (1H, m), 7.00 (1H, d, J=8.4 Hz), 6.66 (1H, t, J=75 Hz),
4.59 (2H, d, J=5.4 Hz), 3.93 (2H, d, J=6.9 Hz), 2.76 (3H, s),
1.33-1.24 (1H, m), 0.70-0.64 (2H, m), 0.41-0.35 (2H, m)
Example 373
The compound obtained in Reference Example 96 was used and treated
following the procedure of Example 96, followed by treatment
according to the procedure of Example 97, yielding white powdery
N-[2-(3-difluoromethoxy-4-hydroxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzam-
ide.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.59 (1H, br s), 8.24 (1H, dd,
J=7.8, 1.2 Hz), 7.81-7.78 (2H, m), 7.63 (1H, s), 7.46-7.40 (1H, m),
7.11-7.05 (2H, m), 6.96 (1H, d, J=8.4 Hz), 6.62 (1H, t, J=75 Hz),
5.87 (1H, br s), 4.62 (2H, d, J=5.4 Hz), 4.19 (2H, q, J=6.9 Hz),
1.50 (3H, t, J=6.9 Hz)
Example 374
Using the compound obtained in Example 373 and 2-bromopropane,
white powdery N-[2-(3-difluoromethoxy-4-isopropoxy
phenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide was obtained following
the procedure of Example 98.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.60 (1H, br s), 8.24 (1H, dd,
J=7.8, 2.1 Hz), 7.85-7.82 (2H, m), 7.64 (1H, s), 7.45-7.39 (1H, m),
7.09-7.01 (2H, m), 6.95 (1H, d, J=8.1 Hz), 6.59 (1H, t, J=75 Hz),
4.71-4.61 (5H, m), 4.19 (2H, q, J=6.9 Hz), 1.51 (3H, t, J=6.9 Hz),
1.40 (6H, d, J=6.9 Hz)
Example 375
Using the compound obtained in Example 373 and
(bromomethyl)cyclopropane, white powdery N-[2-(4-cyclopropyl
methoxy-3-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-ethoxy
benzamide was obtained following the procedure of Example 98.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.59 (1H, br s), 8.24 (1H, dd,
J=7.8, 2.1 Hz), 7.85-7.82 (2H, m), 7.64 (1H, s), 7.45-7.39 (1H, m),
7.09-6.94 (3H, m), 6.66 (1H, t, J=75 Hz), 4.62 (2H, d, J=5.4 Hz),
4.19 (2H, q, J=6.9 Hz), 3.93 (2H, d, J=8.4 Hz), 1.50 (3H, t, J=6.9
Hz), 1.34-1.24 (1H, m), 0.71-0.64 (2H, m), 0.41-0.35 (2H, m)
Example 376
Using the compound obtained in Example 373 and 1-bromopropane,
white powdery N-[2-(3-difluoromethoxy-4-propoxy
phenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide was obtained following
the procedure of Example 98.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.60 (1H, br s), 8.23 (1H, dd,
J=7.8, 1.8 Hz), 7.87-7.83 (2H, m), 7.64 (1H, s), 7.42 (1H, t, J=7.5
Hz), 7.09-6.85 (3H, m), 6.35 (1H, t, J=75 Hz), 4.62 (2H, d, J=6.0
Hz), 4.19 (2H, q, J=6.6 Hz), 4.04 (2H, t, J=6.0 Hz), 1.91-1.84 (2H,
m), 1.50 (3H, t, J=6.9 Hz), 1.07 (3H, t, J=6.9 Hz)
Example 377
Using the compound obtained in Example 373 and allyl bromide, white
powdery N-[2-(4-allyloxy-3-difluoromethoxyphenyl)
oxazol-4-ylmethyl]-2-ethoxybenzamide was obtained following the
procedure of Example 98.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.60 (1H, br s), 8.23 (1H, dd,
J=7.8, 1.8 Hz), 7.86-7.83 (2H, m), 7.64 (1H, s), 7.42 (1H, t, J=7.5
Hz), 7.10-6.97 (3H, m), 6.61 (1H, t, J=75 Hz), 6.07-6.01 (1H, m),
5.49-5.32 (2H, m), 4.68-4.61 (4H, m), 4.19 (2H, q, J=6.9 Hz), 1.50
(3H, t, J=6.9 Hz)
Reference Example 97
Using ethyl 3,4-dihydroxybenzoate and chlorodifluoro methane, white
powdery ethyl 3,4-bis-difluoromethoxybenzoate was obtained
following the procedure of Example 4.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.00-7.90 (2H, m), 7.31 (1H, d,
J=8.1 Hz), 6.60 (1H, t, J=72.9 Hz), 6.57 (1H, t, J=72.9 Hz), 4.39
(2H, q, J=7.2 Hz), 1.40 (3H, t, J=7.2 Hz)
Reference Example 98
Using the compound obtained in Reference Example 97, white powdery
2-(3,4-bis-difluoromethoxyphenyl)-4-chloromethyl oxazol was
obtained following the procedures of Reference Examples 3 to 5.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.95-7.90 (2H, m), 7.73 (1H, s),
7.35 (1H, d, J=8.4 Hz), 6.60 (1H, t, J=72.9 Hz), 6.59 (1H, t,
J=72.9 Hz), 4.57 (2H, s)
Example 378
Using the compound obtained in Reference Example 98, white powdery
3-[2-(3,4-bis-difluoromethoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-
-1-one was obtained following the procedure of Example 190.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.89-7.84 (2H, m), 7.71 (1H, dd,
J=7.5, 1.8 Hz), 7.48-7.41 (2H, m), 7.32 (1H, d, J=8.4 Hz),
7.01-6.93 (2H, m), 6.58 (1H, t, J=75 Hz), 6.57 (1H, t, J=75 Hz),
4.14 (2H, q, J=6.9 Hz), 3.43 (2H, t, J=6.9 Hz), 3.00 (2H, t, J=6.9
Hz), 1.48 (3H, t, J=6.9 Hz)
Reference Example 99
The compound obtained in Reference Example 98 was used and treated
following the procedure of Reference Example 45, followed by
treatment according to the procedure of Reference Example 46,
yielding pale yellow oily [2-(3,4-bis-difluoromethoxy
phenyl)oxazol-4-yl]-methylamine.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.92-7.88 (2H, m), 7.58 (1H, s),
7.34 (1H, d, J=8.4 Hz), 6.60 (1H, t, J=75 Hz), 6.59 (1H, t, J=75
Hz), 3.85 (2H, s)
Example 379
Using the compound obtained in Reference Example 99, white powdery
N-[2-(3,4-bis-difluoromethoxyphenyl)oxazol-4-ylmethyl]-3-methylpicolinami-
de was obtained following the procedure of Example 96.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.61 (1H, br s), 8.40 (1H, dd,
J=7.5, 1.5 Hz), 7.93-7.88 (2H, m), 7.70 (1H, s), 7.60 (1H, d, J=1.5
Hz), 7.58-7.31 (2H, m), 6.60 (1H, t, J=75 Hz), 6.58 (1H, t, J=75
Hz), 4.60 (2H, dd, J=6.0, 1.2 Hz), 2.77 (3H, s)
Example 380
Using the compound obtained in Reference Example 99, white powdery
N-[2-(3,4-bis-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide
was obtained following the procedure of in Example 1.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.59 (1H, br s), 8.23 (1H, dd,
J=7.5, 1.8 Hz), 7.94-7.88 (2H, m), 7.70 (1H, s), 7.46-7.33 (2H, m),
7.07 (1H, t, J=7.5 Hz), 6.95 (1H, d, J=8.4 Hz), 6.60 (1H, t, J=75
Hz), 6.59 (1H, t, J=75 Hz), 4.63 (2H, d, J=6.0 Hz), 4.19 (2H, q,
J=6.9 Hz), 1.50 (3H, t, J=6.9 Hz)
Example 381
Using the compound obtained in Reference Example 98, white powdery
3-[2-(3,4-bis-difluoromethoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)-
propan-1-one was obtained following the procedure of Example
356.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.51 (1H, br s), 7.88-7.85 (2H,
m), 7.59 (1H, d, J=8.4 Hz), 7.53 (1H, s), 7.35-7.30 (2H, m), 6.58
(1H, t, J=75 Hz), 6.57 (1H, t, J=75 Hz), 3.60 (2H, t, J=6.3 Hz),
3.02 (2H, t, J=6.3 Hz), 2.58 (3H, s)
Example 382
Using the compound obtained in Example 347 and the compound
obtained in Reference Example 85, white powdery N-{2-[4-difluoro
methoxy-3-(2,2-difluoroethoxy)phenyl]-oxazol-4-ylmethyl}-2-ethoxy
benzamide was obtained following the procedure of Example 348.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.55 (1H, br s), 8.24 (1H, dd,
J=7.8, 1.8 Hz), 7.71-7.65 (3H, m), 7.46-7.41 (1H, m), 7.29 (1H, s),
7.08 (1H, t, J=8.1 Hz), 6.96 (1H, d, J=8.1 Hz), 6.59 (1H, t, J=74.1
Hz), 6.15 (1H, tt, J=54.9, 4.2 Hz) 4.64 (2H, d, J=5.4 Hz), 4.32
(2H, td, J=12.9, 4.2 Hz), 4.20 (2H, q, J=6.9 Hz) 1.50 (3H, t, J=6.9
Hz)
Example 383
Using the compound obtained in Example 347 and
1,1,1-trifluoro-2-iodoethane, white powdery
N-{2-[4-difluoromethoxy-3-(2,2,2-trifluoroethoxy)phenyl]-oxazol-4-ylmethy-
l}-2-ethoxy benzamide was obtained following the procedure of
Example 348.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.56 (1H, br s), 8.24 (1H, dd,
J=7.8, 1.8 Hz), 7.75-7.68 (3H, m), 7.46-7.40 (1H, m), 7.30 (1H, d,
J=8.4 Hz), 7.08 (1H, t, J=8.1 Hz), 6.96 (1H, d, J=8.1 Hz), 6.60
(1H, t, J=74.1 Hz), 4.63 (2H, d, J=5.4 Hz), 4.49 (2H, q, J=8.1 Hz),
4.20 (2H, q, J=6.9 Hz) 1.50 (3H, t, J=6.9 Hz)
Example 384
Using the compound obtained in Example 17 and 2-bromo propane,
colorless oily
N-[2-(4-methoxy-3-isopropoxyphenyl)oxazol-4-ylmethyl]-3-methylpicoli-
namide was obtained following the procedure of Example 19.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.58 (1H, br s), 8.39 (1H, dd,
J=4.8, 1.2 Hz), 7.63-7.57 (4H, m), 7.33-7.28 (1H, m), 6.93 (1H, d,
J=8.4 Hz), 4.68 (1H, sept., J=6.3 Hz), 4.59 (2H, d, J=5.7 Hz), 3.89
(3H, s), 2.76 (3H, s), 1.41 (6H, d, J=6.3 Hz)
Example 385
Using the compound obtained in Example 347 and
(bromomethyl)cyclobutane, white powdery
N-[2-(3-Cyclobutylmethoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-et-
hoxybenzamide was obtained following the procedure of Example
348.
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.56 (1H, br s), 8.24 (1H, dd,
J=7.8, 1.8 Hz), 7.67-7.58 (3H, m), 7.50-7.40 (1H, m), 7.23 (1H, d,
J=8.4 Hz), 7.08 (1H, t, J=8.1 Hz), 6.96 (1H, d, J=8.1 Hz), 6.63
(1H, t, J=75 Hz), 4.64 (2H, d, J=5.1 Hz), 4.19 (2H, q, J=6.9 Hz),
4.08 (2H, d, J=6.6 Hz) 2.86-2.82 (1H, m), 2.19-2.12 (2H, m),
2.04-1.87 (4H, m), 1.50 (3H, t, J=6.9 Hz)
The chemical structures of the compounds obtained above in the
Reference Examples and Examples are shown below in Tables 1 to
40.
TABLE-US-00001 TABLE 1 ##STR00020## Ref. Ex. No. R.sup.a R.sup.b 5
Methyl Benzyl 11 Methyl ##STR00021## 17 Methyl ##STR00022## 23
Methyl --CH.sub.2CF.sub.3 32 --CH.sub.2CF.sub.3 ##STR00023## 35
Ethyl Ethyl 38 Methyl Methyl 44 --CHF.sub.2 Benzyl 55 Benzyl Benzyl
58 Methyl Ethyl 63 Benzyl Ethyl 68 Methyl iso-Propyl
TABLE-US-00002 TABLE 2 ##STR00024## Ex. No. R.sup.c 1 Benzyl 2 H 3
##STR00025## 4 --CH.sub.2CF.sub.3 5 n-Butyl 6 Cyclopentyl 7
##STR00026## 8 ##STR00027## 9 Ethyl 10 ##STR00028## 11 n-propyl 12
iso-propyl 13 ##STR00029## 14 iso-Butyl 15
--CH.sub.2CH.sub.2CF.sub.3 92 Methyl --OEt: Ethoxy
TABLE-US-00003 TABLE 3 ##STR00030## Ex. No. Ar.sup.a 25
2-Trifluoromethylphenyl 32 2-(2,2,2-Trifluoroethoxy)phenyl 37
2-iso-Propoxyphenyl 38 2-Methylphenyl 39 2-Ethylphenyl 40
2-Chlorophenyl 41 5-Fluoro-2-methoxyphenyl 42
4-Fluoro-2-methoxyphenyl 43 6-Fluoro-2-methoxyphenyl 44
2-Methylthiophenyl 46 2-Methoxyphenyl 47 2-Trifluoromethoxyphenyl
48 2-n-Propoxyphenyl 51 2-n-Butoxyphenyl 52 2-iso-Butoxyphenyl 54
2-Ethylthiophenyl 56 2,6-Dimethoxyphenyl 60
2-Methanesulfonylphenyl
TABLE-US-00004 TABLE 4 ##STR00031## Ex. No. Ar.sup.b 63
2-Methoxyphenyl 64 2-Methylthiophenyl 66 4-Fluoro-2-methoxyphenyl
67 2-iso-Propoxyphenyl 68 6-Fluoro-2-methoxyphenyl 71
2-n-Propoxyphenyl 72 2-n-Butoxyphenyl 73 2-iso-Butoxyphenyl
TABLE-US-00005 TABLE 5 ##STR00032## Ex. No. Ar.sup.c 78
2-Methoxyphenyl 79 2-Methylphenyl 80 2-n-Propoxyphenyl 81
2-iso-Propoxyphenyl 82 4-Chloro-2-methoxyphenyl
TABLE-US-00006 TABLE 6 ##STR00033## Ex. No. Ar.sup.d 85
2-n-Propoxyphenyl 86 2-Trifluoromethylphenyl 88 2-Ethoxyphenyl 89
4-Ethoxyphenyl 90 5-Methoxy-2-trifluoromethoxyphenyl 91
3-Ethoxyphenyl OEt: Ethoxy
TABLE-US-00007 TABLE 7 ##STR00034## Ex. No. Ar.sup.e R.sup.d
R.sup.e 23 2-Trifluoromethylphenyl Methyl Benzyl 24
2-Trifluoromethylphenyl Methyl H 26 2-Trifluoromethylphenyl Methyl
##STR00035## 30 2-(2,2,2- Methyl Benzyl Trifluoroethoxy)phenyl 31
2-(2,2,2- Methyl H Trifluoroethoxy)phenyl 33 2-Methoxyphenyl Methyl
Benzyl 34 2-Methoxyphenyl Methyl H 35 2-Methoxyphenyl Methyl
cyclo-Pentyl 83 2-Ethoxyphenyl --CH.sub.2CF.sub.3 ##STR00036## 93
2-Ethoxyphenyl Methyl Methyl
TABLE-US-00008 TABLE 8 ##STR00037## Ex. No. R.sup.f R.sup.g 16
Methyl Benzyl 17 Methyl H 18 Methyl Cyclopentyl 19 Methyl
--CH.sub.2CF.sub.3 20 Methyl Ethyl 21 Methyl Allyl 22 Methyl
##STR00038## 36 Methyl ##STR00039## 62 Methyl iso-Butyl 84
--CH.sub.2CF.sub.3 ##STR00040## 94 Methyl Methyl 96 --CHF.sub.2
Benzyl 97 --CHF.sub.2 H 98 --CHF.sub.2 ##STR00041## 384 Methyl
iso-Propyl
TABLE-US-00009 TABLE 9 ##STR00042## Ex. No. R.sup.h R.sup.i 27
Ethyl Benzyl 28 Ethyl H 29 Ethyl Cyclopentyl 45 H ##STR00043## 50
Ethyl ##STR00044## 53 iso-Propyl ##STR00045## 57 Methyl
##STR00046## 58 iso-Butyl ##STR00047## 61 n-Propyl ##STR00048## 65
Ethyl iso-Butyl 69 Methyl iso-Butyl 70 iso-Butyl iso-Butyl 74
iso-Propyl iso-Butyl 76 Methyl --CH.sub.2CF.sub.3 77 Ethyl
--CH.sub.2CF.sub.3 95 Methyl Methyl
TABLE-US-00010 TABLE 10 ##STR00049## Ex. No. Ar.sup.f R.sup.j
R.sup.k 49 ##STR00050## Methyl ##STR00051## 55 ##STR00052## Methyl
##STR00053## 59 ##STR00054## Methyl ##STR00055## 75 ##STR00056##
Methyl iso-Butyl 87 ##STR00057## Ethyl Ethyl 99 ##STR00058## Methyl
##STR00059## Me: Methyl
TABLE-US-00011 TABLE 11 ##STR00060## Ex. No. R.sup.l R.sup.m 101
Methyl H 102 Methyl ##STR00061## 103 Methyl Ethyl 104 Methyl Allyl
105 Methyl Cyclopentyl 106 Methyl iso-Butyl 107 Methyl n-Propyl 108
Methyl ##STR00062## 109 Methyl n-Butyl 110 Methyl ##STR00063## 111
Methyl iso-Propyl 112 Methyl --CH.sub.2CF.sub.3 113 Methyl
##STR00064## 114 Methyl ##STR00065## 115 Methyl ##STR00066## 116
Methyl ##STR00067## 117 Methyl ##STR00068## 118 Methyl ##STR00069##
119 Methyl ##STR00070## 120 Methyl ##STR00071## 121 Methyl
##STR00072## 122 Methyl ##STR00073## 182 Ethyl Ethyl 190 Benzyl
Ethyl 191 H Ethyl 192 iso-Propyl Ethyl 228 --CHF.sub.2 Benzyl 229
--CHF.sub.2 H 230 --CHF.sub.2 iso-Propyl --OEt: Ethoxy
TABLE-US-00012 TABLE 12 ##STR00074## Ex. No R.sup.n 169 iso-Propyl
170 ##STR00075## 171 Cyclopentyl 172 Ethyl 173 iso-Butyl 174 Allyl
175 --CH.sub.2CF.sub.3 --OMe: Methoxy
TABLE-US-00013 TABLE 13 ##STR00076## Ex. No. R.sup.o 194 H 195
Ethyl 196 Cyclopentyl 197 iso-Propyl 198 ##STR00077## 199
##STR00078## 200 Allyl 201 ##STR00079## 203 --CH.sub.2CF.sub.3
TABLE-US-00014 TABLE 14 ##STR00080## Ex. No. R.sup.p 207 H 208
##STR00081## 209 Ethyl 210 iso-Propyl 211 Allyl 212 ##STR00082##
213 --CH.sub.2CF.sub.3 214 ##STR00083##
TABLE-US-00015 TABLE 15 ##STR00084## Ex. No. R.sup.q 164 Benzyl 166
Allyl 177 ##STR00085## 189 Ethyl 224 iso-Propyl
TABLE-US-00016 TABLE 16 ##STR00086## Ex. No. R.sup.r 220 H 221
##STR00087## 225 Ethyl 226 Allyl 227 iso-Propyl
TABLE-US-00017 TABLE 17 ##STR00088## Ex. No. Ar.sup.g 178
2-Allyloxyphenyl 184 3-Ethoxyphenyl 185 4-Ethoxyphenyl 205
2-n-Propoxyphenyl 216 2-iso-Propoxyphenyl 218 2-Methylphenyl --OEt:
Ethoxy
TABLE-US-00018 TABLE 18 Ex. No. Chemical Structure 165 ##STR00089##
168 ##STR00090## 176 ##STR00091## 179 ##STR00092## 223 ##STR00093##
231 ##STR00094## 232 ##STR00095## 233 ##STR00096## 234 ##STR00097##
235 ##STR00098##
TABLE-US-00019 TABLE 19 ##STR00099## Ex. No. R.sup.s 136 H 137
##STR00100## 138 Ethyl 139 iso-Propyl 140 Allyl 141 ##STR00101##
142 iso-Butyl 143 n-Propyl 144 Cyclopentyl 145 ##STR00102## 146
##STR00103## 147 n-Butyl 148 ##STR00104## 149 ##STR00105## 150
--CH.sub.2CH.sub.2Ph 151 --CH.sub.2CH.sub.2CH.sub.2Ph 152
##STR00106## 153 ##STR00107## 154 ##STR00108## 155
--CH.sub.2CF.sub.3 156 ##STR00109## 157 ##STR00110## 158 Cyclohexyl
159 ##STR00111## Ph: Phenyl
TABLE-US-00020 TABLE 20 ##STR00112## Ex. No. R.sup.t R.sup.u 125
Methyl H 126 Methyl ##STR00113## 127 Methyl iso-Butyl 128 Methyl
Cyclopentyl 129 Methyl --CH.sub.2CF.sub.3 131 Ethyl H 132 Ethyl
Cyclopentyl 133 Ethyl ##STR00114## 134 Ethyl iso-Butyl
TABLE-US-00021 TABLE 21 Ex. No. Chemical Structure 123 ##STR00115##
161 ##STR00116## 162 ##STR00117## 163 ##STR00118## 181 ##STR00119##
183 ##STR00120## 187 ##STR00121## 188 ##STR00122##
TABLE-US-00022 TABLE 22 ##STR00123## Ex. No. Ar.sup.h R.sup.v
R.sup.w 193 2-n-Propoxyphenyl Methyl Benzyl 202 2-n-Propoxyphenyl
Methyl --CH.sub.2CF.sub.3 204 2-n-Propoxyphenyl Ethyl Ethyl 206
2-iso-Propoxyphenyl Methyl Benzyl 215 2-iso-Propoxyphenyl Ethyl
Ethyl 217 2-Methylphenyl Ethyl Ethyl 219 2-Methylphenyl Methyl
Benzyl 222 2-Benzyloxyphenyl Methyl iso-Propyl
TABLE-US-00023 TABLE 23 ##STR00124## Ex. No. Ar.sup.i R.sup.x
R.sup.y 100 2-Ethoxyphenyl Methyl Benzyl 124 3-Methoxypyridyl
Methyl Benzyl 130 3-Ethoxypyridyl Methyl Benzyl 135 3-Methylpyridyl
Methyl Benzyl 160 2-Pyridyl Methyl Benzyl 167 2-MethoxyPhenyl
Methyl Benzyl 180 3-MethylPyridyl Ethyl Ethyl 186 3-MethylPyridyl
Benzyl Benzyl
TABLE-US-00024 TABLE 24 Ex. No. Chemical Structure 236 ##STR00125##
237 ##STR00126## 238 ##STR00127## 239 ##STR00128## 240
##STR00129##
TABLE-US-00025 TABLE 25 Ex. No. Chemical Structure 241 ##STR00130##
242 ##STR00131## 243 ##STR00132## 244 ##STR00133## 245
##STR00134##
TABLE-US-00026 TABLE 26 Ex. No. Chemical Structure 246 ##STR00135##
247 ##STR00136## 248 ##STR00137## 249 ##STR00138## 250
##STR00139##
TABLE-US-00027 TABLE 27 Ex. No. Chemical Structure 251 ##STR00140##
252 ##STR00141## 253 ##STR00142## 254 ##STR00143## 255 ##STR00144##
256 ##STR00145##
TABLE-US-00028 TABLE 28 Ex. No. Chemical Structure 257 ##STR00146##
258 ##STR00147## 259 ##STR00148## 260 ##STR00149## 261
##STR00150##
TABLE-US-00029 TABLE 29 Ex. No. Chemical Structure 262 ##STR00151##
263 ##STR00152## 264 ##STR00153## 265 ##STR00154##
TABLE-US-00030 TABLE 30 Ref. Ex. No. Chemical Structure 89
##STR00155## 90 ##STR00156## 91 ##STR00157## 92 ##STR00158## 93
##STR00159## 95 ##STR00160##
TABLE-US-00031 TABLE 31 Ref. Ex. No. Chemical Structure 96
##STR00161## 98 ##STR00162## 99 ##STR00163##
TABLE-US-00032 TABLE 32 ##STR00164## Ex. No. R.sub.A R.sub.B 325
Methyl 1-Ethylpropyl 346 Difluoromethyl Benzyl 347 Difluoromethyl H
348 Difluoromethyl iso-Butyl 349 Difluoromethyl Ethyl 350
Difluoromethyl n-Propyl 351 Difluoromethyl Allyl 352 Difluoromethyl
iso-Propyl 353 Difluoromethyl Cyclopropylmethyl 354 Difluoromethyl
3-Butenyl 355 Difluoromethyl 1-Ethylpropyl 373 H Difluoromethyl 374
iso-Propyl Difluoromethyl 375 Cyclopropylmethyl Difluoromethyl 376
n-Propyl Difluorornethyl 377 Allyl Difluoromethyl 380
Difluoromethyl Difluoromethyl 382 Difluoromethyl 2,2-Difluoroethyl
383 Difluoromethyl 2,2,2-Trifluoroethyl 385 Difluoromethyl
Cyclobutylmethyl OEt: Ethoxy
TABLE-US-00033 TABLE 33 ##STR00165## Ex. No. R.sub.C R.sub.D 324
Methyl 1-Ethylpropyl 338 Difluoromethyl Ethyl 339 Difluoromethyl
Allyl 340 Difluoromethyl n-Propyl 341 Difluoromethyl iso-Propyl 342
Difluoromethyl 1-Ethylpropyl 343 Difluoromethyl 3-Butenyl 344
Difluoromethyl iso-Butyl 345 Difluoromethyl Cyclobutylmethyl 367 H
Difluoromethyl 368 Allyl Difluoromethyl 369 Cyclobutylmethyl
Difluoromethyl 370 iso-Butyl Difluoromethyl 371 3-Butenyl
Difluoromethyl 379 Difluoromethyl Difluoromethyl
TABLE-US-00034 TABLE 34 ##STR00166## Ex. No. R.sub.E R.sub.F 313
Methyl Difluoromethyl 314 Methyl 2,2-Difluoroethyl 315 Methyl
2-Fluoro ethyl 334 Difluoromethyl Ethyl 335 Difluoromethyl Allyl
336 Difluoromethyl Cyclopropylmethyl 337 Difluoromethyl 3-Butenyl
363 H Difluoromethyl 364 3-Butenyl Difluoromethyl 365 Allyl
Difluoromethyl 366 Ethyl Difluoromethyl 378 Difluoromethyl
Difluoromethyl OEt: Ethoxy
TABLE-US-00035 TABLE 35 ##STR00167## Ex. No. R.sub.G R.sub.H 308
Methyl Difluoromethyl 309 Methyl 2,2-Difluoroethyl 310 Methyl
2-Fluoroethyl 311 Methyl sec-Butyl 312 Methyl 1-Ethylpropyl 317 H
2,2-Difluoroethyl 318 Ethyl 2,2-Difluoroethyl 319 iso-Propyl
2,2-Difluoroethyl 327 Difluoromethyl H 328 Difluoromethyl
Cyclopropylmethyl 329 Difluoromethyl n-Propyl 330 Difluoromethyl
Allyl 331 Difluoromethyl 3-Butenyl 332 Difluoromethyl iso-Propyl
333 Difluoromethyl Ethyl 356 H Difluoromethyl 357 iso-Propyl
Difluoromethyl 358 Allyl Difluoromethyl 359 3-Butenyl
Difluoromethyl 360 Cyclopropylmethyl Difluoromethyl 361 n-Propyl
Difluoromethyl 362 Ethyl Difluoromethyl 381 Difluoromethyl
Difluoromethyl
TABLE-US-00036 TABLE 36 ##STR00168## Ex. No. R.sub.I R.sub.J
R.sub.K 267 Methyl Benzyl Difluoromethyl 268 Methyl Benzyl
2-Fluoroethyl 269 Methyl Benzyl 2,2-Difluoroethyl 270 Methyl H
Difluoromethyl 271 Methyl H 2-Fluoroethyl 272 Methyl H
2,2-Difluoroethyl 273 Methyl iso-Propyl Difluoromethyl 274 Methyl
Ethyl Difluoromethyl 275 Methyl iso-Propyl 2-Fluoroethyl 276 Methyl
3-Butenyl 2-Fluoroethyl 277 Methyl iso-Butyl 2-Fluoroethyl 278
Methyl iso-Propyl 2,2-Difluoroethyl 279 Methyl n-Propyl
2,2-Difluoroethyl 280 Methyl Ethyl 2,2-Difluoroethyl 281 Methyl
Allyl 2,2-Difluoroethyl 282 Methyl 3-Butenyl 2,2-Difluoroethyl 283
Methyl Cyclopropylmethyl 2,2-Difluoroethyl 284 Methyl
2,2-Difluoroethyl 2,2-Difluoroethyl 285 Methyl iso-Butyl
2,2-Difluoroethyl 288 Ethyl Ethyl Difluoromethyl 289 Ethyl Ethyl
2-Fluoroethyl 290 Ethyl Ethyl 2,2-Difluoroethyl 292 Ethyl Ethyl
Trifluoromethyl 293 Methyl Cyclopropylmethyl Trifluoromethyl
TABLE-US-00037 TABLE 37 Ex. No. Chemical Structure 266 ##STR00169##
286 ##STR00170## 287 ##STR00171## 291 ##STR00172## 294 ##STR00173##
295 ##STR00174##
TABLE-US-00038 TABLE 38 Ex. No. Chemical Structure 296 ##STR00175##
297 ##STR00176## 298 ##STR00177## 299 ##STR00178## 300 ##STR00179##
301 ##STR00180## 302 ##STR00181## 303 ##STR00182##
TABLE-US-00039 TABLE 39 Ex. No. Chemical Structure 304 ##STR00183##
305 ##STR00184## 306 ##STR00185## 307 ##STR00186## 316 ##STR00187##
320 ##STR00188## 321 ##STR00189##
TABLE-US-00040 TABLE 40 Ex. No. Chemical Structure 322 ##STR00190##
323 ##STR00191## 326 ##STR00192##
Test Example 1
Phosphodiesterase (PDE)4 Inhibitory Activity Evaluation Test
(1) Large Scale Plasmid Preparation
Plasmid containing genes (HPDE4D) coding for human PDE4D3 cDNA
(stored in Otsuka America Pharmaceutical, Inc., Maryland Research
Laboratories) was transformed in E. coli, cultured on a large
scale, and purified using an EndoFree.TM. Plasmid Maxi Kit
(Qiagen).
(2) Abundant Expression and Purification of PDE4D
COS-7 cells derived from African green monkey kidneys were passage
cultured in D-MEM media containing 100 units/ml penicillin, 100
.mu.g/ml streptomycin, and 10% FBS. The cells were transfected with
the plasmid prepared in (1) above using Lipofectamine.TM. 2000
(hereinafter referred to as "LF2000", Invitrogen), following the
manufacturer's protocol. The COS-7 cells were inoculated in a 10 cm
culture dish on the previous day so as to be 90% confluent on the
day of transfection. Culture dishes each containing a plasmid
solution (solution A) in which 24 .mu.g of plasmid was diluted in
1.5 ml Opti-MEM I Reduced Serum Medium (Invitrogen) and an LF2000
solution (solution B) in which 60 .mu.l of LF2000 was diluted in
1.5 ml Opti-MEM I Reduced Serum Medium were separately allowed to
stand for 5 minutes at room temperature. Solutions A and B were
then mixed and the mixture was allowed to stand for 20 minutes at
room temperature. The mixture was added to the cultured cells, and
incubated at 37.degree. C. (5% CO.sub.2) overnight. On the
following day, the medium was replaced, and the mixture was further
incubated overnight to harvest the cells in the following manner.
The cells were washed with PBS (Sigma) once, and 10 ml of a
Trypsin-EDTA solution (Sigma) was added to each culture dish. After
the solution was distributed to each of the culture dishes, the
cells were detached, and the dishes were allowed to stand for about
5 minutes at 37.degree. C. The detached cells from the dishes were
suspended in media, collected into centrifuge tubes, and
centrifuged at 1200 rpm for 5 minutes at 4.degree. C., and
supernatants were removed. The cells were further washed with PBS,
and stored at -80.degree. C. KHEM buffer (100 mM Hepes, 50 mM KCl,
10 mM EGTA, 1.92 mM MgCl.sub.2, pH 7.4) containing 1 mM DTT, 1
.mu.g/ml antipain, 1 .mu.g/ml aprotinin, 1 .mu.g/ml leupeptin, 1
.mu.g/ml pepstatin A, 157 .mu.g/ml benzamidine, and 120 .mu.g/ml
Pefabloc SC was added to the stored cells, and the contents were
moved to a glass homogenizer to be homogenized on ice. The cell
suspension was centrifuged at 1000 rpm for 5 minutes at 4.degree.
C., and the supernatant was further centrifuged at 14000 rpm for
one hour. After centrifugation, the supernatant was dispensed into
new tubes as PDE4D enzyme solutions, and stored in a deep
freezer.
(3) Determination on Dilution Ratio of PDE4D Enzyme Solutions
The PDE4D enzyme solutions prepared in (2) above were dissolved in
20 mM Tris-HCl solution (pH 7.4) to give 10-, 25-, 50-, 100-, 200-,
400-, and 800-fold dilutions of the enzyme solutions. PDE4D
activities were measured according to (4) below. The percentage of
catalyzed cAMP to total cAMP was calculated, and such a dilution,
in which the percentage was between 10% and 30%, was adopted in the
inhibitory study below.
(4) Measurement of PDE4D Inhibitory Activity
Necessary amounts of test compounds were weighed, and 100%
dimethylsulfoxide (DMSO) was added thereto to adjust the
concentration to 10 mM. The solutions were stored in a freezer as
stock solutions of each test compound. After being thawed when
required, the solutions were diluted 20-fold with 100% DMSO to give
a 500 .mu.M concentration. Further, 10-fold serial dilutions were
made with 100% DMSO to prepare test compounds of different
concentrations. 2 .mu.l of solutions containing one of each of the
test compound were separately added into 1.2 ml tubes in which 23
.mu.l of 20 mM Tris-HCl (pH 7.4) had been placed beforehand. 25
.mu.l of a PDE4D enzyme solution diluted at an optimal ratio
determined in (3) above were added on ice to each of the tubes, and
50 .mu.l of a substrate solution containing 2 .mu.M[.sup.3H] cAMP
prepared by dilution with a 20 mM Tris-HCl (pH 7.4) containing 10
mM MgCl.sub.2 was added thereto. The final DMSO concentration in
the reaction liquid was 2%. After mixing, the mixture was incubated
for 10 minutes at 30.degree. C. At the completion of the
incubation, the tubes were placed in a bath containing boiling
water for 3 minutes, and the reaction was stopped. After cooling
the tubes in ice, 25 .mu.l solution of 0.2 mg/ml snake venom was
added thereto, and after mixing the mixture was incubated for 10
minutes at 30.degree. C. At the completion of the incubation, 0.4
ml of a Dowex 1.times.8 resin solution prepared in an EtOH:H.sub.2O
(1:1) solution was added thereto. After mixing, the tubes were
allowed to stand at room temperature for at least an hour. 50 .mu.l
of the supernatant in one of each of the tubes was moved to one of
the wells of a topcount plate, and the plate was dried overnight.
.sup.3H radioactivity (cpm) was measured using a TopCount.TM..
The IC.sub.50 values (concentration which produced 50% inhibition
of substrate hydrolysis) for the test compounds were determined
with the Excel (Microsoft Excel 2000 SR-1) statistical package
using regression analysis function.
The results are shown in Table 41. The table demonstrates that
compounds represented by formula (1) have the outstanding PDE4
inhibitory activities.
In the structural formulae shown in the following table, -Me is a
methyl group, -Et is an ethyl group, --OMe is a methoxy group,
--OEt is an ethoxy group, and --SMe is a methylthio group.
TABLE-US-00041 TABLE 41 PDE 4 Ex. No. Chemical Structure
(IC.sub.50: nM) 3 ##STR00193## <50 14 ##STR00194## <50 18
##STR00195## <50 19 ##STR00196## <50 21 ##STR00197## <50
22 ##STR00198## <50 29 ##STR00199## <50 32 ##STR00200##
<50 35 ##STR00201## <50 36 ##STR00202## <50 42
##STR00203## <50 43 ##STR00204## <50 44 ##STR00205## <50
61 ##STR00206## <50 62 ##STR00207## <50 63 ##STR00208##
<50 76 ##STR00209## <50 98 ##STR00210## <50 99
##STR00211## <50 102 ##STR00212## <50 103 ##STR00213## <50
104 ##STR00214## <50 108 ##STR00215## <50 111 ##STR00216##
<50 112 ##STR00217## <50 116 ##STR00218## <50 126
##STR00219## <50 129 ##STR00220## <50 132 ##STR00221## <50
133 ##STR00222## <50 137 ##STR00223## <50 138 ##STR00224##
<50 139 ##STR00225## <50 140 ##STR00226## <50 141
##STR00227## <50 143 ##STR00228## <50 146 ##STR00229## <50
153 ##STR00230## <50 155 ##STR00231## <50 157 ##STR00232##
<50 159 ##STR00233## <50 166 ##STR00234## <50 169
##STR00235## <50 170 ##STR00236## <50 172 ##STR00237## <50
174 ##STR00238## <50 177 ##STR00239## <50 181 ##STR00240##
<50 182 ##STR00241## <50 195 ##STR00242## <50 208
##STR00243## <50 224 ##STR00244## <50 232 ##STR00245## <50
274 ##STR00246## <50 275 ##STR00247## <50 276 ##STR00248##
<50 278 ##STR00249## <50 280 ##STR00250## <50 281
##STR00251## <50 283 ##STR00252## <50 284 ##STR00253## <50
285 ##STR00254## <50 289 ##STR00255## <50 290 ##STR00256##
<50 299 ##STR00257## <50 304 ##STR00258## <50 305
##STR00259## <50 309 ##STR00260## <50 311 ##STR00261## <50
312 ##STR00262## <50 314 ##STR00263## <50 315 ##STR00264##
<50 318 ##STR00265## <50 324 ##STR00266## <50 328
##STR00267## <50 329 ##STR00268## <50 330 ##STR00269## <50
331 ##STR00270## <50 332 ##STR00271## <50 333 ##STR00272##
<50 334 ##STR00273## <50 335 ##STR00274## <50 336
##STR00275## <50 337 ##STR00276## <50 338 ##STR00277## <50
339 ##STR00278## <50 340 ##STR00279## <50 341 ##STR00280##
<50 342 ##STR00281## <50 343 ##STR00282## <50 344
##STR00283## <50 345 ##STR00284## <50 348 ##STR00285## <50
349 ##STR00286## <50 350 ##STR00287## <50 351 ##STR00288##
<50 352 ##STR00289## <50 353 ##STR00290## <50 354
##STR00291## <50 355 ##STR00292## <50 382 ##STR00293## <50
383 ##STR00294## <50 384 ##STR00295## <50
Test Example 2
Inhibitory Activity Measurement on TNF-.alpha. Production
TNF-.alpha. production inhibitory activity was evaluated according
to the following tests.
(1) Isolation of Mononuclear Cells from Mouse Peripheral Blood
Mononuclear cells were isolated from heparinized blood obtained
from male BALB/c mice (Charles River Laboratories, Japan) by
density gradient centrifugation using Lympholyte-M (Cedarlane
Laboratories). Viable cell numbers in the peripheral blood
mononuclear cells were counted using trypan blue dye, and prepared
in cell culture medium (RPMI 1640 medium containing 10% FCS) to
1.25.times.10.sup.6 cells/ml.
(2) Induction of TNF-.alpha. Production
Test compounds were dissolved in DMSO, and test compound solutions
were diluted for use in cell culture media. 20 .mu.l test compound
solutions of different concentrations and 160 .mu.l peripheral
blood mononuclear cell suspensions were placed in a 96-well plate,
and cultured for 30 minutes. 20 .mu.l (final concentration 1
.mu.g/ml) lipopolysaccharide (LPS) derived from E. coli (serotype
055:B5) was added thereto to induce THF-.alpha. production. The
mixtures were then cultured at 37.degree. C. for 5 hours, and the
culture supernatant was removed from each well.
(3) Measurement of TNF-.alpha. Concentration
TNF-.alpha. concentrations in the culture supernatants were
measured by ELISA (OptEIA.TM. Set Mouse TNF-.alpha., BD
Pharmingen). The IC.sub.50 values (concentration which produced 50%
inhibition of TNF-.alpha. production) for the test compounds were
determined with the Excel (Microsoft Excel 2000 SR-1) statistical
package using regression analysis function.
The results obtained are shown in table 42.
TABLE-US-00042 TABLE 42 Test compounds TNF-.alpha. (IC.sub.50: nM)
Compound of Ex. 18 <50 Compound of Ex. 43 <50 Compound of Ex.
126 <50 Compound of Ex. 157 <50 Compound of Ex. 177
<50
* * * * *
References